Activity-dependent regulation of MHC class I expression in the developing primary visual cortex of the common marmoset monkey

Adema Ribic; Gabriele Flügge; Christina Schlumbohm; Kerstin Mätz-Rensing; Lutz Walter; Eberhard Fuchs

doi:10.1186/1744-9081-7-1

Activity-dependent regulation of MHC class I expression in the developing primary visual cortex of the common marmoset monkey

Ribic, Adema; Flügge, Gabriele; Schlumbohm, Christina; Mätz-Rensing, Kerstin; Walter, Lutz; Fuchs, Eberhard 2011-01-04 00:00:00 Background: Several recent studies have highlighted the important role of immunity-related molecules in synaptic plasticity processes in the developing and adult mammalian brains. It has been suggested that neuronal MHCI (major histocompatibility complex class I) genes play a role in the refinement and pruning of synapses in the developing visual system. As a fast evolutionary rate may generate distinct properties of molecules in different mammalian species, we studied the expression of MHCI molecules in a nonhuman primate, the common marmoset monkey (Callithrix jacchus). Methods and results: Analysis of expression levels of MHCI molecules in the developing visual cortex of the common marmoset monkeys revealed a distinct spatio-temporal pattern. High levels of expression were detected very early in postnatal development, at a stage when synaptogenesis takes place and ocular dominance columns are formed. To determine whether the expression of MHCI molecules is regulated by retinal activity, animals were subjected to monocular enucleation. Levels of MHCI heavy chain subunit transcripts in the visual cortex were found to be elevated in response to monocular enucleation. Furthermore, MHCI heavy chain immunoreactivity revealed a banded pattern in layer IV of the visual cortex in enucleated animals, which was not observed in control animals. This pattern of immunoreactivity indicated that higher expression levels were associated with retinal activity coming from the intact eye. Conclusions: These data demonstrate that, in the nonhuman primate brain, expression of MHCI molecules is regulated by neuronal activity. Moreover, this study extends previous findings by suggesting a role for neuronal MHCI molecules during synaptogenesis in the visual cortex. Background ß-2-microglobulin subunit, and a short peptide compris- The major histocompatibility complex (MHC) is a dense ing 8-15 amino acids that is derived from self or foreign cluster of genes found in all jawed vertebrates that antigens [4,5]. In this form, MHCI modulates immune encodes a great number of proteins involved in immune response by interacting in trans with a large number of responses [1,2]. A group of these genes, MHC class I, immune receptors [6]. Additionally, MHCI heavy chains codes for transmembrane glycoproteins responsible for can be detected under certain conditions on the cell sur- presentation of antigenic peptides to cytotoxic CD8+ T face without ß-2-microglobulin and peptide [6]. It is lymphocytes [3]. MHC class I (MHCI) proteins are typi- thoughtthatinthis “free heavy chain” form, MHCI cally heterotrimers composed of a polymorphic trans- molecules may interact in cis with certain receptors and membrane heavy chain (HC), a noncovalently attached thereby regulate their trafficking [6-8]. Virtually all nucleated cells express MHCI proteins, usually in their heterotrimeric form; however, their expression on neu- * Correspondence: aribic@cnl-dpz.de † Contributed equally rons was always debated [9]. Despite the controversy, Clinical Neurobiology Laboratory, German Primate Center/Leibniz Institute neuronal expression of MHCI under certain conditions for Primate Research, Kellnerweg 4, Göttingen 37077, Germany has been reported [10,11] and recent findings on Full list of author information is available at the end of the article © 2011 Ribic et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 2 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 involvement of neuronal MHCI in brain development elimination, but rather in synaptogenesis. These results and synaptic plasticity were of great surprise [12-15]. not only validate the potentially important role of neuro- These and other studies begun to unravel the previously nal MHCI molecules in visual cortex development, but unknown and complicated mechanisms of interactions also point to interesting interspecies differences in their between the central nervous and the immune system distribution, and potentially their function. that may have great clinical implications [16]. Although MHCI genes are well conserved among Methods mammals, there are a number of differences in the orga- Animals nization, structure, and function of these genes between Thirty-six common male marmoset monkeys (Callithrix rodents and primates, including humans [17]. The first jacchus) were investigated. The animals were obtained study on the function of MHCI molecules in the central from the breeding colony at the German Primate Center nervous system (CNS) proposed a role for them in the (Göttingen, Germany). All investigations and the experi- removal of excess synapses in the developing visual sys- ments were performed to the highest ethical standards tem [15]. The visual system displays two forms of plasti- according to the relevant local, national and interna- city: visual input-driven, activity-dependent plasticity tional regulations concerning the use of animals. All and activity-independent plasticity [18]. The develop- research projects were carried out only with authoriza- ment of the main structures of the visual system, the tion from the relevant ethics committees. We employed thalamus and the primary visual cortex (V1), are at least the minimum number of animals required to obtain at certain developmental stages dependent on the activ- consistent data and to avoid animal suffering. For the ity coming from the retina [19,20]. The thalamic dorso- termination of non-human primates, the legal require- lateral geniculate nucleus (LGN) is the first relay ments, guidelines and recommendations set by the structure of visual input and is organized into segre- national authorities were followed strictly. The use of gated, eye-specific neuronal layers that form upon sti- animals including non-human primates in research in mulation by early spontaneous activity of retinal Germany is based on the “Tierschutzgesetz” (Animal th ganglion cells [19]. Neurons of the LGN send their pro- Protection Law) of the 25 of May, 1998 (BGBl.I Nr.30 jections to V1 where their activity is needed in proper v.29.5.1998, S. 1105) and the EU guidelines 86/609/EEG. development of eye-specific populations of neurons The proposals for research conducted in this study are assembled in the ocular dominance columns (ODCs; approved by the local Government and a specially [18]). Blockade of activity of one eye during develop- appointed Ethical Review Committee (Niedersächsisches ment of the visual circuits while leaving the other one Landesamt für Verbraucherschutz und Lebensmittelsi- intact (monocular deprivation) perturbs the segregation cherheit, permit numbers 33.11.425-04-003/08 and of the LGN neurons into eye-specific layers [19,21]. In 33.11.425-04-026/07). V1, as a consequence of visual deprivation, the popula- For expression studies, animals of the following ages tion of neurons responsive to the intact eye increases were used [25,26]: postnatal days 1 and 7, and postnatal [18,22]. Monocular deprivation by means of tetrodo- months 1, 3, 5, 7, 12, and 21 (N = 3 per age). For mono- toxin-induced block of retinal activity downregulates cular enucleation (ME), the left eyes of one month-old MHCI expression levels in the LGN [15]. Furthermore, marmoset monkeys (N = 6; approximate body weight it was reported that MHCI molecules are indispensable 75 g) were surgically enucleated under general anesthe- for developmental refinement in the LGN, i.e. for sia. As anesthesia, the animals received 0.1 ml of a pre- removal of excess synapses during normal development mix containing 4 mg/ml alphaxalon and 1.33 mg/ml [12,23]. Asides from differences in the structure and alphadolon (Saffan ; Schering-Plough Animal Health, function of MHCI genes, primates and rodents differ Welwyn Garden City, UK), 0.37 mg/ml diazepam, and significantly in terms of structure of their visual systems 0.015 mg/ml glycopyrroniumbromid (Robinul ; Riemser, [24]. To gain an insight into the role of MHCI molecules Germany). Enucleation was carried out as described for in the nonhuman primate brain, we investigated the spa- pet animals [27] and the eyehole was filled with Gelas- tiotemporal pattern of expression of MHCI genes in the typt sponge (Sanofi-Aventis, Frankfurt, Germany) as primary visual cortex of the common marmoset monkey. soon as arterial bleeding was no longer visible. The Our data confirmed that MHCI molecules are expressed wound was closed with an intracutane suture of vicryl in the developing visual cortex of the marmoset monkey 6-0 (V302H; Ethicon, Norderstedt, Germany). Directly and that their levels are regulated by neuronal activity. after surgery (day 0) and at days 3 and 5, all animals However, the temporal pattern of their expression during received an antibiotic (amoxicillin-trihydrate; Duphamox development of the V1 and their expression levels upon LA , Fort Dodge, Würselen, Germany). ME animals and monocular enucleation indicated that MHCI molecules six age-matched controls were sacrificed at five months investigated here may not be involved in synapse of age [28]. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 3 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Brain sections (Promega, Madison, WI, USA) for the antisense and For in situ hybridization, brains were immediately sense probe, respectively, in the presence of 9.25 MBq removed from terminally anesthetized animals [overdose of P-UTP (Hartmann Analytic GmbH, Braunschweig, of ketamine (50 mg/ml), xylazine (10 mg/ml), and atro- Germany; specific activity, 3,000 Ci/mmol) for 1 h at pine (0.1 mg/ml)] and the whole visual cortices were 37°C. Probes were purified using Microspin S-400 HR quickly dissected (area determined according to [29,30]), columns (Amersham Pharmacia, Freiburg, Germany) embedded in Tissue Tek (Sakura Finetek, Heppenheim, and hybridization buffer (50% deionized formamide, 10% Germany), flash frozen in liquid nitrogen, and stored at dextran sulphate, 0.3 M NaCl, 1 mM EDTA, 10 mM -80°C. Frozen brains were sectioned using a cryostat Tris-HCl, pH 8.0, 500 μg/ml tRNA, 0.1 M dithiothreitol, (Leica CM3050, Bensheim, Germany) and coronal sec- and 1 × Denhardt’ssolution) wasadded to yieldafinal tions (10 μm) of whole visual cortices were thaw- probe activity of 5 × 10 cpm. The hybridization mix- mounted on adhesive silane-coated slides (Histobond, ture containing the probe was denatured at 70°C for Marienfeld, Laboratory Glassware, Lauda-Königshofen, 10 min, cooled to 55°C, and pipetted directly onto sec- Germany). For immunohistochemistry, marmosets that tions (80 μl/section). Hybridization was performed for were terminally anesthetized (see above), were perfused 18 h at 68°C. Sections were subsequently washed in 4 × transcardially with 0.9% saline, followed by 200 ml of SSC (0.6 M NaCl, 0.06 M citric acid), 2 × SSC, and 0.5 fixative containing 4% paraformaldehyde in 0.1 M × SSC for 10 min each at 37°C. After incubation (1 h at sodium-phosphate buffer (pH 7.2) for 15 min. The 75°C) in 0.2 × SSC, sections were washed twice in 0.1 × heads were postfixed in the same fixative, and brains SSC, once at 37°C and again at RT, for 10 min each. were carefully removed from the skulls on the following Finally, sections were dehydrated through graded alco- day. After cryoprotection in 0.1 M phosphate-buffered hols, air dried, and exposed to Bio-Max MR film (Amer- saline (PBS; 0.1 mM phosphate buffer, 0.9% NaCl, pH sham Pharmacia) for three days at 4°C. Films were 7.2) containing 30% sucrose, serial coronal sections of developed and fixed with GBX (Kodak, Rochester, NJ, theentirevisualcortices (thickness:40 μmfor expres- USA). sion studies and 60 μm for ME animals and controls) were obtained using a cryostat. Quantitative in situ hybridization After in situ hybridization, sections were coated with PCR cloning of MHCI transcripts photoemulsion (Kodak NBT2, Rochester, NJ, USA) at The isolation of the common marmoset MHC class I 42°C, dried for 90 min at RT, and stored for seven heavy chain cDNA sequences was carried out using weeks at 4°C in a lightproof container. Exposed slides reverse transcriptase polymerase chain reaction (RT- were developed at 15°C for 5 min (Kodak developer D- PCR). One microgram of total brain RNA was reverse 19), rinsed twice briefly in H O, and fixed for 5 min at transcribed using the oligo (dT) primer and 400 U of RT (fixer, Kodak Polymax). Sections were counter- reverse transcriptase (Promega, Mannheim, Germany). stained either with 0.05% toluidine blue in 0.1% diso- An aliquot of this reaction was used as a template in a dium tetraborate (Sigma) for expression studies or with PCR containing primers designed with the Primer3 soft- methyl green (Sigma) for monocular enucleation studies, ware [31]. Primers were devised to amplify full-length cleared in xylol, and coverslipped using mounting med- marmoset MHC class I heavy chain transcripts (acces- ium (Eukitt, Kindler, Freiburg, Germany). Hybridized sion number: U59637). Primer sequences also included sections were visualized with a 40× objective (NA = 1.4; BamHI restriction sites and were as follows: forward 5’- Zeiss) under a light microscope (Axioscope, Zeiss) and CACGGATCCCACTTTACAAGCCGTGAGAGAC-3’, silver grain quantification was performed on a cell-by- reverse 5’-CACGGATCCCTCCTGTTGCTCTCGGG cell basis using ImageJ (U.S. National Institutes of GGCCTTG-3’. Caja-G*1 (accession number: U59637) Health, Bethesda, Maryland, USA). Images were was obtained and cloned into the pDrive vector obtained from layer IV neurons and, for each area (Qiagen). within the primary visual cortex (demarcated according to [29,30]) two images were acquired, i.e., one using a In situ hybridization green filter to eliminate background staining from Cryosections (10 μm) of visual cortices were dried at RT methyl green and one using white light to later precisely for 20 min, fixed in 4% buffered paraformaldehyde localize neuronal nuclei. A circular counting mask of (PFA, pH 7.2), rinsed in PBS, acetylated (0.1 M trietha- 15 μm in diameter was used to delineate the region of nolamine, 0.25% acetic acid anhydride), washed in PBS, interest and was placed over neuronal nuclei during and dehydrated through a graded ethanol series. Caja-G counting. Relative optical density (ROD) threshold plasmid DNA was linearized and riboprobes were intensities were optimized to detect exposed silver synthesized using T7 and SP6 RNA polymerases grains exclusively. The silver grain density within the Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 4 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 region of interest was measured. Grain density was com- asinglePCR product[33].All products were run on pared between layer IV neurons in primary visual cor- 2.5% agarose gels to confirm a single product (Addi- tices of six animals (three slides per animal, minimum tional file 1). The Caja-G PCR product was additionally 300 neurons per animal were counted) using Student’st sequenced using the BigDye Terminator Sequencing Kit test (GraphPad Prism version 4 for Windows, GraphPad (Applied Biosystems) and forward primer in order to Software, San Diego, CA, USA). confirm its identity (Additional File 2). The relative abundance of the MHCI-HC, c-Fos and GFAP mRNA Quantitative RT-PCR transcripts was calculated relative to the mRNA levels of To isolate RNA for RT-PCR, brains were immediately the internal reference gene b-actin and was compared removed from terminally anesthetized animals (see between both left and right cortices of control and enu- above) and whole occipital lobes containing visual cor- cleated animals using Student’s t-test (GraphPad Prism tices were quickly dissected. Total RNA was isolated version 4 for Windows). from both hemispheres of dissected tissue samples from animals at the age of five months (N = 3 controls and N Immunocytochemistry for light microscopy = 3 unilaterally enucleated animals) using the QIAGEN Coronal cryosections (40 μm for expression studies and RNeasy kit (Qiagen, Hilden, Germany) according to the 60 μm for ME animals) of occipital lobes were collected manufacturer’s instructions. As the cortices had to be and washed briefly in PBS before the epitope retrieval separated during RNA isolation due to their size, both step. Epitope retrieval was performed by incubating the left and right hemispheres of all animals were treated as sections for 20 min in 10 mM sodium citrate buffer pre- independent samples. The integrity and quantity of puri- heated to 80°C. Sections were later brought to RT, fied RNA was assessed by spectrophotometry. Comple- washed in PBS, and quenched of endogenous peroxidase mentary DNA (cDNA) was synthesized from mRNA activity using 30 min incubation at RT in 0.5% H O in 2 2 transcripts using oligo (dT) primers and Superscript distilled water. Sections were then washed in PBS, 12-18 II reverse transcriptase (Invitrogen, Karlsruhe, Ger- blocked for 1 h at RT (3% normal horse serum in PBS), many), according to the manufacturer’s instructions. incubated for 16 h at 4°C with mouse monoclonal The Primer3 software v2.0 [31] was used to design TP25.99 or Q1/28 IgG [34,35] kindly provided by S. gene-specific primers, with amplicons ranging from 50 Ferrone, University of Pittsburgh, USA), 1:300 dilution to 150 bp in length. The primers used for the detection in 3% normal horse serum in PBS; monoclonal mouse of MHC class I heavy chain transcripts were: forward 5’- W6/32 [36], 1:300 dilution in 3% normal horse serum in GTGATGTGGAGGAAGAACAGC-3’, reverse 5’-CACT PBS; monoclonal rabbit anti c-Fos (Cell Signalling Tech- TTACAAGCCGTGAGAGA-3’ (CajaG*01, accession nologies, Beverly, MA, USA); monoclonal anti-GFAP number U59637). Primers for the detection of GFAP (Sigma) 1:200 dilution in 0.01% Triton-X 100 and 3% were: forward 5’-AAACGAGTCCCTGGAGAG-3’, normal horse serum in PBS; or control mouse IgG reverse 5’-TCCTGGTACTCCTGCAAGT-3’ (marmoset (Sigma), and washed again. For c-Fos, W6/32 and GFAP GFAP, Ensembl transcript number ENSCJAT00 staining, the epitope retrieval step was not performed. 000024380). Primers for the detection of c-Fos were: Sections were then incubated with biotinylated horse forward 5’-CGAAGGGAAAGGAATAAGAT-3’, reverse anti-mouse IgG or donkey anti-rabbit IgG (Vector 5’-GCAGACTTCTCATCTTCCAG-3’ (marmoset c-Fos, Laboratories, Burlingame, CA, USA), 1:200 dilution in Ensembl transcript number ENSCJAT00000040535). Pri- 3% normal horse serum in PBS, for 1 h at RT. After mers for the detection of b-actin were: forward 5’- washing, sections were incubated with avidin-biotin CATCCGCAAAGACCTGTATG-3’, reverse 5’-GGAG- horseradish peroxidase (Vectastain Elite ABC Kit, Vector CAATGACCTTGATCTTC-3’ (marmoset ß-actin, acces- Laboratories, Burlingame, CA, USA), 1:100 dilution in sion number DD279463). A quantitative analysis of gene 3% normal horse serum in PBS, for 1 h at RT, washed expression was performed using the 7500 Real-time in PBS and then again in 0.05 M Tris/HCl (pH 7.2) PCR apparatus (Applied Biosystems, Darmstadt, Ger- prior to DAB detection (DAB detection with or without many) in combination with Quantitect SYBR green nickel enhancement was performed according to the technology (Qiagen). The light cycler was programmed manufacturer’s instructions; DAB-Kit, Vector Labora- to the following conditions: an initial PCR activation tories). Sections were washed in 0.05 M Tris/HCl (pH step of 10 min at 95°C, followed by 40 cycling steps 7.6) and again in 0.1 M PBS prior to xylol clearance, (denaturation for 15 s at 95°C, annealing for 30 s at 55° dehydration, and coverslipping with Eukitt mounting C, and elongation for 60 s at 72°C). Details of the quan- medium (Kindler). For identification of cortical layers, titative real-time PCR were described previously [32]. sections adjacent to the ones used for immunocyto- Dissociation curves were generated for all PCR products chemistry were stained with toluidine-blue (Sigma). to confirm that SYBR green emission was detected from Digital images of stained sections were acquired using Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 5 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 an Axiophot II microscope (Zeiss). Final images were antibodies) displayed only background fluorescence assembled in Corel PhotoPaint X3 and, in case of higher (data not shown). magnifications, were a composition of 4-5 images along the longitudinal axis of the primary visual cortex Protein extraction [29,30]. Contrast and luminosity were adjusted in Corel Brains were immediately removed from terminally PhotoPaint X3 for images obtained from monocularly anesthetized animals (see above), and the whole visual enucleated animals. cortices were quickly dissected. Whole visual cortex samples were homogenized with a Dounce homogenizer Immunofluorescence and confocal microscopy (tight pestle) in ice-cold homogenization buffer consist- Antibodies used in double-labeling experiments were ing of 50 mM Tris/HCl pH 7.4, 7.5% glycerol, 150 mM applied sequentially and blocking steps were performed NaCl, 1 mM EDTA, 1% Triton-X 100, and complete using normal sera of the host species from which the protease inhibitor cocktail (Roche Diagnostics, Man- respective secondary antibodies were derived. Cryostat nheim, Germany). After homogenization, the samples sections (40 μm) of occipital lobes were rinsed in PBS were centrifuged at 4,000× g for 20 min at 4°C. The before the epitope retrieval step was performed, as resulting supernatant was centrifuged again until it was described above. Nonspecific antibody binding sites clear. Protein concentration was measured using the were blocked with 3% normal serum in PBS for 1 h at Bio-Rad DC Protein assay (Bio-Rad Laboratories, Her- RT. Sections were then incubated with mouse monoclo- cules, CA, USA). nal TP25.99 antibody, 1:300 in 3% normal serum in PBS, for 16 hrs at 4°C, washed, and incubated in sec- Immunoblot analysis ondary antiserum (Alexa 488-coupled goat anti-mouse, Protein preparations were electrophoresed in 12.5% Molecular Probes, Invitrogen, Leiden, Netherlands) at a SDS gels under reducing conditions. Proteins were dilution of 1:500 for 4 h in a lightproof container. Sec- subsequently transferred to nitrocellulose membranes tions were then washed and incubated with either rabbit (Schleicher and Schuell, Dassel, Germany) via semidry anti-MAP2 antibody (1:200, Synaptic Systems, Göttin- electroblotting for 2 h at 1 mA/cm in transfer buffer gen, Germany), rabbit anti-NMDAR1 (1;200, Synaptic containing 25 mM Tris-base, 150 mM glycine, and Systems), rabbit anti-GFAP (1:500, Synaptic Systems), or 10% (v/v) methanol. After the transfer, the blotted rabbit anti-vimentin antibody (1:200, Synaptic Systems) membranes were blocked with 5% (w/v) milk powder in 3% normal serum in PBS for 16 h at 4°C. For GFAP- and 0.1% Tween-20 in PBS for 1 h at RT and were vimentin colocalization studies, the epitope retrieval step then incubated with either monoclonal TP25.99 was not performed and following primary antibodies (1:1,000) or monoclonal anti-SNAP-25 (1:1,000, Synap- were used: rabbit anti-vimentin (1:200, Synaptic Sys- tic Systems) antibodies overnight at 4°C. After washing tems) and mouse anti-GFAP (1:200, Sigma). Sections three times for 5 min in PBS/0.1% Tween-20, blots were then washed and incubated 4 h at RT in secondary were incubated for 1 h at RT with horseradish peroxi- antiserum (Alexa 568-coupled goat anti-rabbit, Molecu- dase-coupled goat anti-mouse IgG (1:4,000, Santa Cruz lar Probes, Invitrogen) diluted 1:500 in 3% normal Biotechnology, Santa Cruz, USA). Prior to visualiza- serum in PBS. Thereafter, sections were washed in PBS tion, blots were washed in PBS/0.1% Tween-20 (3 × and floated/mounted on SuperFrost Plus slides (Men- 5 min) and once more in PBS. Signals were visualized zel-Gläser GmbH, Braunschweig, Germany) in distilled using SuperSignal West Dura enhanced luminescence water, allowed to dry overnight at 4°C, and coverslipped substrate (Pierce Biotechnology, Rockford, IL, USA). with mounting medium (Aqua-Polymount, Polysciences Membranes were subsequently stripped in a mixture of Inc., Warrington, PA, USA). For control sections, the b-mercaptoethanol and SDS in PBS and incubated same procedures were performed omitting the primary with monoclonal anti-b-actin antibody (1:4000, Sigma). antibody. For controls, the same procedures were performed Confocal microscopy was performed using a laser- using the mouse IgG (Sigma) instead of a primary anti- scanning microscope (LSM 5 Pascal, Zeiss) with an body. Control IgG yielded no signals in the Western argon 488 nm laser and a helium/neon 543 nm laser (in blot (data not shown). For quantification, blots were multiple-tracking mode). High magnification, single visualized with MCID Basic software (Imaging optical plane images of layer IV neurons of the primary Research Inc., St. Catherines, Ontario, Canada) so that visual cortex [29,30] or of the subcortical white matter nonsaturating bands were obtained. Quantification was in the occipital lobes were obtained at a resolution of performed using the gel analysis plug-in of ImageJ 1,024 × 1,024 with an Apochromat 63× oil objective (U.S. National Institutes of Health, Bethesda, Mary- (NA = 1.4) and immersion oil (Immersol, Zeiss; refrac- land, USA). Values obtained for MHCI and SNAP-25 tive index = 1.518). The control sections (no primary were normalized to ß-actin values. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 6 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Image analysis of sections from monocularly enucleated animals Digital images of immunostained tissue sections were acquired using an Axiophot II microscope (Zeiss). Images were taken from the V1 areas of right visual cor- tices. Variations in MHCI immunoreactivity through layer IV were measured as described previously [37]. Briefly, images were normalized and black-white inverted using ImageJ (U.S. National Institutes of Health, Bethesda, MD, USA) and regions within layer IV that encompassed the thickness of the entire layer IV (2 mm in length and approximately 1 mm in thickness) were defined as the regions of interest. For identification of cortical layers, sections adjacent to the ones used for immunocytochemistry were stained with toluidine-blue (Sigma). The density profile of layer IV in the primary visual cortex (region demarcated according to [29,30]) was obtained using ImageJ. Values were averaged (using the four closest neighbors) and plotted as a function of the distance along layer IV parallel to the pia mater. After delineating the borders of immunoreactive Figure 1 Lack of MHCI-HC expression in the lateral geniculate patches, their width was measured using ImageJ and nucleus as revealed by in situ hybridization. Autoradiograph of a brain section of a 7 days-old marmoset from the level of the lateral compared using Student’s t-test (GraphPad Prism ver- geniculate nucleus (LGN) processed for in situ hybridization (left) sion 4 for Windows). and toluidine-blue stained section (right). Note the absence of MHCI-HC signals in the LGN (delineated with arrowheads). Results Abbreviations: Dentate gyrus, DG; postnatal day, PD. Scale bar: Expression of MHCI molecules in LGN and V1 of the 1 mm. common marmoset To investigate the expression of MHCI genes in the marmoset LGN and primary visual cortex, a full-length remained the same throughout postnatal months 12 and clone of the heavy chain (HC) of the classical marmoset 21 (data not shown). Emulsion autoradiography revealed MHCI gene Caja-G [accession number U59637 [38]) the presence of silver grains clustered over single cells was used for in situ hybridization experiments. Animals in layer IV of the primary visual cortex (Figure 2B). were chosen based on age and according to the main However, with this technique, the number of labeled stages of visual system development [25,26] and were of cells appeared relatively low because the liquid photo the following ages: postnatal days 1 and 7; and postnatal emulsion that is used for dipping the radiolabeled sec- months 1, 3, 5, 7, 12, and 21. Although LGN develop- tions is less sensitive to the radioactivity than the auto- ment occurs in utero in primates [39,40], we expected radiographic films. The sense probe was used as a to observe strong expression of MHCI-HC (MHCI control and it yielded no signal, thus demonstrating the heavy chain) in newborn animals, as the expression of specificity of the MHCI-HC antisense probe (Figure 2A these genes persists in the LGN of adult rodents and and 2B). cats [12,15].Toour surprise,there wasalmost no Antibodies against marmoset MHCI proteins are not MHCI-HC signal in the marmoset LGN, even after long available; however, because of the high similarity of exposures to autoradiographic films (Figure 1). However, these proteins with their human homologues, we used in situ hybridization revealed a strong expression of the well characterized TP25.99 antibody for the detec- MHCI-HC throughout the visual cortex. On postnatal tion of marmoset MHCI proteins [34,35]. The epitope day 7, this expression was mainly concentrated in layers to which this antibody binds is situated in the a-3 I and IV of both primary and secondary visual cortex domain of MHCI molecules, which is monomorphic [V1 and V2, Figure 2A; regions demarcated according to and the most conserved domain across all species [34]. [29,30]) and in the subcortical white matter (Figure 2A This domain is almost identical between marmosets and and 2B). In older animals (1 to 7 months of age), the humans. Moreover, the TP25.99 antibody is also one of signal became more diffuse, with cells in all cortical theantibodiesthatrecognize thefreeheavychain form layers exhibiting MHCI-HC gene expression (Figure 2A of MHCI [41,42]. TP25.99 recognized a band of and 2B). This pattern of MHCI-HC mRNA expression approximately 45 kDa on Western blots, which is the Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 7 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 2 Expression of MHCI-HC in the primary visual cortex as revealed by in situ hybridization. A) Autoradiographs of visual cortices processed for in situ hybridization. Sections represent the main stages of visual cortex development. The expression of MHCI-HC in the 7 days-old animal (PD7) decreases with progressing age (compare with 7 months-old animal, PM7). Primary visual cortex (V1) is delineated with white dashed lines. Layer IV and subcortical white matter are delineated with white lines. Abbreviations: Postnatal day, PD; postnatal month, PM; primary visual cortex, V1; secondary/prestriate visual cortex, V2; subcortical white matter, SWM; layer IV, IV. Scale bar: 1 mm. B) Upper row: Toluidine-blue stained section of a 7 days-old animal (left) after in situ hybridization, and autoradiograph of the same section (middle panel; film autoradiography) reveal MHCI-HC signals in layers I and IV-VI of the primary visual cortex and in the subcortical white matter (SWM). Emulsion autoradiography (right) reveals silver grains clustered over single cells (arrowheads). Middle row: Toluidine-blue stained section of a 1-month old animal (left) after in situ hybridization and autoradiograph of the same section (middle panel) revealed MHCI-HC signals in all cortical layers and in the subcortical white matter (SWM). Emulsion autoradiography (right) reveals silver grains clustered over single neurons (arrowheads). Bottom row: Sense probe revealed only background signals (left; film autoradiograph) and background levels of silver grains in emulsion autoradiography (right). Roman numerals denote cortical layers. Scale bar for film autoradiographs: 1 mm. Scale bar for emulsion autoradiography: 20 μm. Abbreviations: Postnatal day, PD; postnatal month, PM; primary visual cortex, V1; subcortical white matter, SWM. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 8 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 expected molecular weight of the MHCI-HC (Figure 3A). Protein expression was quantified in animals aged one, three, and five months, which represent the main stages of synaptogenesis, namely the initial, the peak and the refinement stage [26]. MHCI-HC protein levels at these stages coincided with levels of the synaptogen- esis marker SNAP-25 (Figure 3B and [43]). Immunocy- tochemistry revealed a strong MHCI-HC staining of neurons throughout the primary visual cortex of a 7 months-old animal (Figure 4) and the same staining pat- tern was observed in all developmental stages (data not shown). To further demonstrate that MHCI-HC protein expression in the primary visual cortex is neuronal, we performed double-labeling experiments using TP25.99 and an antibody against microtubule associated protein 2 (MAP2), which is an established dendritic marker [44-46]. A punctuate pattern of MHCI-HC immunor- eactivity that colocalized with MAP2-positive neuronal Figure 4 MHCI-HC immunoreactivity in the primary visual cortex of the common marmoset. Representative coronal section of the primary visual cortex of a 7 months-old marmoset probed with TP25.99 antibody (mouse anti-human MHCI) revealing strong staining of neurons in all layers (left). Roman numerals denote cortical layers. Control mouse IgG showed no reaction (right). Scale bar: 200 μm. Abbreviations: Postnatal month, PM; subcortical white matter, SWM; primary visual cortex, V1. processes was observed in the neuronal somata, den- drites and neuropil in the main thalamorecipient layer of V1, layer IV (Figure 5). As previously reported [23], MHCI-HC protein partially colocalized with both gephyrin and SAP102, markers of inhibitory and excita- tory synapses respectively ([47-50]; Additional file 3). In situ hybridization also showed strong MHCI-HC gene expression in the subcortical white matter in the occipi- tal lobes, consistent with previous studies on MHCI in the visual cortex of cats [15]. This region contains spe- cialized glial cells, radial glia, involved in neuronal differentiation and migration [51]. Double-labeling experiments using antibodies against MHCI-HC and Figure 3 MHCI-HC protein levels at different stages of visual vimentin, a marker of radial glia [52,53] confirmed that cortex development. The antibody TP25.99 (mouse anti-human MHCI-HC is indeed expressed on radial glia in the sub- MHCI) recognized bands of appropriate size for MHCI-HC protein cortical white matter (Figure 6). Vimentin-positive cells (MHCI-HC, A) in Western blots of proteins extracted from the also displayed strong immunoreactivity for GFAP (glial marmoset visual cortex. Animals were 1, 3 and 5 months old (PM1, fibrillary acidic protein) in the subcortical white matter 3, 5) representing the main stages of synaptogenesis: initial stage, peak and rapid decline/synaptic refinement, respectively. SNAP-25 ([54]; Additional file 4), but vimentin immunoreactivity was used as a marker of synatogenesis. Data were normalized to ß- could only be detected in this region. No vimentin-posi- actin. Molecular weights (in kDa) are indicated on the left side. Data tive cells and only GFAP immunoreactivity was detected are from three independent experiments with N = 1 animal per in the visual cortex (Additional file 4). The MHCI-HC stage (B). Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 9 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 5 MHCI-HC protein colocalizes with the neuronal marker MAP-2 in layer IV neurons of the V1. MHCI-HC (green; A) is localized mainly to the neuronal somata in the primary visual cortex, where it colocalizes with MAP-2 (red; B and C). Higher magnification of the area indicated by the dashed line in C reveals MHCI clustered over MAP2-positive neurons and processes (arrowheads; D). Scale bar in C: 50 μm; scale bar in D: 25 μm. Abbreviations: postnatal month 7, PM7; primary visual cortex, V1. signal in the V1 did not colocalize with GFAP-positive [56,57], further suggested that neurons might express astrocytes (Additional file 4). However, fully assembled MHC class I molecules preferentially in their free heavy heterotrimeric MHCI molecules could be detected on chain form on the cell surface. Unfortunately, we could microglial cells in the cortex with W6/32 antibody not reliably detect ß-2-microglobulin subunit with the (Additional file 5). W6/32 is a prototypic anti-MHC antibodies available to us (data not shown), although we class I antibody that binds to a conformational epitope have detected ß-2-microglobulin transcripts in the mar- on MHCI heavy chains upon their association with b-2- moset cortex in our previous study [56]. microglubulin and the peptide [36,41,55]. Interestingly, another antibody that recognizes free heavy chains, Expression levels of MHCI molecules are regulated by monoclonal Q1/28 [34] recognized neuronal-like pro- neuronal activity cesses and cell bodies in the marmoset cortex (Addi- Several previous studies suggested a variety of nonim- tional file 5). This, along with our previous studies mune roles for MHCI molecules, most of which refer to Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 10 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 6 MHCI-HC colocalizes with radial glia marker in the subcortical white matter of the occipital lobes.MHCI-HC (green;A) is localized to vimentin-positive radial glia (red; B and C) in the subcortical white matter (SWM). Higher magnification reveals colocalization between MHCI-HC and vimentin signals (white arrowheads in D). Scale bar in C: 50 μm; scale bar in D: 25 μm. Abbreviations: postnatal month 1, PM1; subcortical white matter, SWM. involvement of MHCI free heavy chain form in receptor levels were significantly higher in the visual cortices of trafficking, cell growth and differentiation [7]. As the enucleated animals, as determined by qRT-PCR (quanti- temporal and spatial pattern of MHCI expression corre- tative Real Time Polymerase Chain Reaction, Figure 7). lates with synaptogenesis in the primary visual cortex, Also, quantitative in situ hybridization using the Caja-G we decided to study this further. Enucleation of one eye probe confirmed the qRT-PCR results revealing a higher before critical stages of visual cortex development density of silver grains over cells in layer IV of the pri- induces significant morphological and physiological mary visual cortex of the enucleated animals (Figure 8A changes in V1 [18,22]. Monocular deprivation, induced and 8B). by either unilateral enucleation or by other means (eye-- lid suture or pharmacological blockade of retinal activ- Neurons with higher MHCI-HC expression receive ity), causes the intact eye to dominate the V1, both afferents from the intact eye anatomically and physiologically [18]. Dendritic arbors In situ hybridization was not able to shed light as to of the neurons in V1 receiving afferents from the where the elevated MHCI-HC transcript levels are loca- deprived eye shrink [58]. This shrinkage presumably lized, in neurons receiving afferents from the intact or reduces the width of ODCs subserving the deprived eye from the enucleated eye. Hence, in order to localize [18,58,59]. On the other hand, ODCs subserving the MHCI-HC expression in the V1 of the enucleated ani- intact eye expand [60-63]. It is known that synaptic mals, we performed immunohistochemistry using the input regulates gene expression in target neurons and TP25.99 antibody. Control animals (5 months old) dis- previous gene expression studies have reported major played a relatively uniform staining pattern throughout activity-dependent changes in the expression of numer- V1 (Figure 9A). In contrast, TP25.99 revealed a patchy ous genes [64,65]. We used monocular enucleation pattern of immunoreactivity in V1 of enucleated animals (ME) to induce the aforementioned changes in V1 of (Figure 9Band Additional file 6). To assign the regions the marmoset. Animals were enucleated at one month of high and low immunoreactivity to neurons receiving and were sacrificed at five months of age [28]. MHCI- afferents from either the intact or the enucleated eye, HC gene expression in visual cortices of monocularly we stained adjacent sections for a known activity- enucleated animals and age-matched controls were com- marker, a method commonly employed in monocular pared using qRT-PCR with MHCI-HC PCR primers deprivation paradigms [66,67]. For this study, we used designed to recognize the intracellular domain of Caja- c-Fos as a marker of neuronal activity [68,69]. Expres- G. Both left and right visual cortices were used from all sion of both c-Fos and MHCI-HC was uniform, albeit at animals. In the present study, MHCI-HC transcript a very low level in control animals (Figure 9A and 9B). Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 11 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 7 MHCI-HC mRNA expression is upregulated in response to monocular enucleation. qRT-PCR reveals a significant difference in MHCI-HC mRNA expression levels in the whole visual cortices of animals that have undergone monocular enucleation (ME) and controls. Data are expressed as mean ± SEM (standard error of the mean) and are representative of three independent experiments performed with samples isolated from both hemispheres of N = 3 animals/group. Significant differences between groups as determined by Student’s two-tailed t-test: *, p < 0.05 (t = 2.961 df = 10). However, in animals that had undergone monocular enucleation, column-like patches of c-Fos and MHCI- HC immunoreactivity were visible throughout layer IV of V1 (Figure 9C and 9D and Additional file 6). Com- parison of adjacent sections stained for MHCI-HC and c-Fos showed that the columns with high MHCI-HC immunoreactivity overlap with regions of high c-Fos immunoreactivity (Figure 9C and 9D and Additional file 6). Secondary visual cortex (V2) displayed no such col- umn-like patches, neither in c-Fos nor in MHCI-HC staining (data not shown). Although the patchy appear- ance of MHCI-HC immunoreactivity was encompassing not only layer IV, but also layers II and III, we measured the optical density profiles only in layer IV since this is the main recipient layer. In sections from the enucleated animals, the MHCI-HC optical density profile from the entire layer IV in V1, measured along its horizontal axis (Figure 10A), displayed variations in intensity that were Figure 8 Monocular enucleation upregulates MHCI-HC mRNA not observed in control animals (Figure 10B). Regions in layer IV of the primary visual cortex. A: Numbers of silver grains per cell reveal elevated levels of MHCI-HC expression in layer with high and low immunoreactivity were detected in IV of the V1 of enucleated animals (ME). Data are expressed as these subjects. In contrast, control animals displayed a mean ± SEM (standard error of the mean), N = 3 animals/group. relatively weak and uniform staining of all layers (Figure Significant differences between groups as determined by Student’s 9A; Figure 10B). As it was previously shown that col- two-tailed t-test: *, p < 0.05 (t = 3.781, df = 4). B: Examples of umns with neurons receiving afferents from the intact sections from layer IV of the primary visual cortex of a control and an enucleated animal showing silver grains over cells (circular eye are wider and occupy larger regions in V1, we mea- counting mask). Scale bar: 20 μm. Abbreviations: Postnatal month 5, sured the width of columns exhibiting high and PM5; primary visual cortex, V1. low MHCI-HC immunoreactivity [61]. A significant Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 12 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 9 Primary visual cortex reveals a banded pattern of MHCI-HC and c-Fos immunoreactivity in enucleated animals. A-D: Patches of stained neurons can be observed in enucleated (C and D), but not in control animals (A and B). These patches are detected with the MHCI antibody (C) and with the c-Fos antibody (D). Asterisks in C and D denote identical blood vessels. Roman numerals indicate cortical layers. Abbreviation: primary visual cortex, V1; monocularly enucleated animal, ME. Note: Black horizontal lines in the lower parts of C and D indicate areas with high MHCI-HC and c-Fos immunoreactivity; white lines point to low immunoreactivity areas. difference was found between the widths of columns high expression levels of this gene are associated with exhibiting high and low immunoreactivity, with stronger high neuronal activity. MHCI-HC staining intensity localized in the wider col- umns (Figure 10C). Furthermore, a number of previous Discussion studies have associated the expression of NMDAR1 (N- Several recent studies have implicated MHCI proteins in methyl D-aspartate receptor subunit 1) with develop- the elimination of excess synapses in the visual system mental plasticity in the visual cortex [37,61,70]. After during distinct phases of cortical development monocular deprivation, higherlevelsofNMDAR1are [12,15,23]. MHCI molecules, as well as the organization present on neurons that still receive visual input and of the visual system, differ between rodents and pri- afferents from the intact eye [37,61,70]. In the present mates, including humans [17,24]. We therefore investi- study, MHCI-HC protein was localized on NMDAR1- gated the expression of neuronal MHCI molecules in positive neurons in V1 of enucleated animals, which the brain of the common marmoset monkey. To the further supports the notion that MHCI-HC expression best of our knowledge, the present study is the first to levels are associated with neuronal activity (Additional characterize the spatio-temporal pattern of MHCI gene file 7). Interestingly, transcript levels of the activity mar- expression in the primary visual cortex during postnatal ker c-Fos [68,69] were also significantly elevated in the development in a nonhuman primate. enucleated animals, similar to MHCI-HC levels (Addi- tional file 8). These results confirm the hypothesis that Expression and localization of MHCI molecules in V1 the columns with high MHCI-HC immunoreactivity It is known that virtually all nucleated cells express receive afferents from the intact eye, suggesting that MHCI molecules in form of completely assembled Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 13 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 10 MHCI-HC is upregulated in primary visual cortex neurons that receive afferents from the intact eye. A: Example of the region analyzed for optical density measurements (delineated with white, dashed line). Abbreviations: primary visual cortex, V1; monocularly enucleated animal, ME. B: Optical density profiles recorded from layer IV of the primary visual cortex of a control animal (black dotted line) and two enucleated animals (red and blue dotted lines). C: Width of MHCI-HC immunoreactive column-like patches showing that the wider columns display stronger MHCI-HC staining indicating that MHCI-HC levels are elevated in neurons receiving afferents from the intact eye. Difference between the groups is highly significant as determined by Student’s two tailed t-test: **, p < 0.01 (t = 5.166 df = 4). Data are expressed as mean ± SEM (standard error of the mean), N = 3 animals/group, 12 measurements per animal. Note: Black horizontal lines in (A) and (B) indicate areas with high MHCI-HC immunoreactivity, while white lines point to low immunoreactivity areas. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 14 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 heterotrimers, and in some cases in form of the peptide- situ hybridization that revealed a distinct spatio-tem- free heavy chains [4,6]. The present study clearly poral pattern of MHCI-HC expression, the staining pat- showed that MHCI molecules are expressed on MAP-2 tern generated with the TP25.99 antibody was rather positive neurons of V1. However, in this and our pre- uniform throughout all cortical layers and developmen- vious studies [56,57], we were only able to detect neuro- tal stages. While the MHCI subset-specific riboprobe nal expression of MHCI heavy chain proteins. In used for in situ hybridizationverylikelytargetedonlya addition, in situ hybridization and immunohistochemis- few MHCI genes, the antibody we used for histochem- try revealed high expression levels of MHCI-HC ical detection of MHCI targets the most conserved, throughout the subcortical white matter (SWM) of the monomorphic part of these molecules. Hence, the occipital lobes, consistent with what has previously been TP25.99antibodylikelyrecognized a large number of observed in cats [15]. In SWM, MHCI-HC protein colo- MHCI-HC proteins expressed on V1 neurons, including calized with vimentin-positive radial glial cells. These the ones targeted at the mRNA level by in situ hybridi- highly specialized cells are regarded as neuronal precur- zation riboprobe. As previously mentioned, the common sors and are involved in proper development and migra- marmoset MHCI gene cluster is not yet fully character- tion of cortical neurons [51]. In primates, these cells are ized and so far only two loci have been described, the also GFAP-positive from early prenatal stages, but can classical Caja-G and the non-classical Caja-E [38]. Based be distinguished from astrocytes on the basis of their on this (Additional file 2) and our previous studies distinct morphology and localization [71]. We did not [56,57], we believe that the neuronal MHCI-HC detect any vimentin-positive cells in the cortical layers, detected in the present study is a classical marmoset and MHCI-HC was not expressed in GFAP-positive cor- MHCI, Caja-G. Nonetheless, the levels of MHCI-HC tical astrocytes (Additional file 4), although these astro- protein expression in the visual cortex correlated well cytes were stained with the antibody that recognized with the levels of SNAP-25 (synaptosome-associated fully assembled, heterotrimeric form of MHCI (Addi- protein 25 kDa). This protein is an established synapto- tional file 5). These findings further implicate MHCI in genesis marker [43,75,76] and the present data on proper development of the visual cortex, although their SNAP-25 protein expression levels confirmed previous potential function in this context remains elusive [72]. findings that synapse density in the marmoset V1 As the marmoset MHCI gene cluster is not fully charac- reaches very high values in the third postnatal month, terized yet, we hope that future studies will shed light followed by a rapid decline due to synapse elminiation on the exact identity and potential functional differences [25,26]. Contrary to our expectations and to the pro- between neuronal, radial glial and microglial MHCI. posed role for MHCI in the elimination of synapses Previous studies have shown that MHCI proteins may [12,15,23], MHCI-HC protein expression was at its peak be localized to both pre- and postsynaptic sites already in the third postnatal month, together with [14,23,57,73,74]. The MHCI-HC molecules detected SNAP-25 levels, and was in decline in the fifth postnatal here with confocal microscopy and TP25.99 antibody month. This suggests that, as recently proposed [74], seem to be associated with the postsynaptic sites (cell MHCI proteins may exert their function during synapto- bodies and dendrites, Figure 5) and they displayed no genesis, rather than during refinement and elimination obvious preference for excitatory vs inhibitory synapses of synapses. (Additional file 3), as has previously been reported [23]. MHCI expression in the visual cortex is activity dependent MHCI-HC mRNA and protein expression in the developing As genetic manipulation of primates is still either una- visual cortex vailable or at an early stage [77], we used monocular In contrast to the previous studies in rodents and cats deprivation as an alternative model to further clarify the [12,15], we did not detect expression of MHCI-HC in role of MHCI molecules in the marmoset visual cortex. the LGN at postnatal stages used in this study. It is pos- Prolonged monocular deprivation induced by various sible that MHCI genes are expressed prenatally in the means (in the order of months) induces morphological marmoset LGN, as the segregation of LGN layers in pri- changes in the visual cortex because neurons that mates occurs in utero [39,40]. Furthermore, the probe receive input from the intact eye expand their connec- used here for the detection of MHCI-HC transcripts is tions and cortical space at the expense of neurons that specific for a subset of MHCI molecules, while the receive afferents from the deprived eye [21,60]. A num- probes used in previous studies were mostly pan-specific ber of studies have shown that monocular deprivation and therefore detected a larger variety of MHCI mole- results in the upregulation of growth factors and genes cules [15]. Even so, the present data showed that MHCI associated with neuronal degeneration or synaptogenesis genes are strongly expressed throughout all regions of [64,65,78]. In mice, monocular deprivation increases the visual cortex of the marmoset. In contrast to the in levels of SNAP-25 and SynCAM (synaptic cell adhesion Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 15 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 molecule) transcripts [78], both of which are required MHCI in the visual system, the very large number of for synaptogenesis [79-81]. Interestingly, MHCI-HC these genes and the fact that there are no true ortholo- transcript levels detected in the present study after gues between rodents and primates [17] makes direct monocular enucleation with qRT-PCR and in situ hybri- comparisons very difficult. On the other hand, the pos- dization for classical marmoset MHCI-HC were also sible interspecies differences in function are not sur- higher in response to monocular enucleation. The levels prising. MHCI molecules exhibit a multitude of of neuronal activity marker c-Fos were also elevated. On functions and may, for example, transmit both activat- the contrary, GFAP displayed no significant change in ing and inhibitory signals in the immune system [7,84]. either expression levels or in expression pattern in enu- MHCI proteins are also necessary for immunological cleated animals (Additional file 9). This even further synapse formation [85]. In addition to their role in correlated MHCI-HC levels with neuronal activity, and synaptic refinement and stripping, MHCI molecules not with microglial activation. have been implicated in stabilization of certain types of We used immunohistochemistry to localize the ele- terminals in the peripheral nervous system of mice vated MHCI-HC levels to neurons receiving afferent [86]. The exact mechanism and role of MHCI in the inputs from the intact eye. In V1 of enucleated animals, visual cortex is yet to be elucidated, although previous both the well-established activity marker c-Fos [68,69] studies have shown that MHCI may associate with PI- and MHCI-HC immunostaining revealed a pattern of 3, which is known to be a synaptogenic molecule column-like patches, where regions of high c-Fos and [8,87]. Another possibility includes the MHCI-present- high MHCI-HC immunoreactivity overlapped and were ing peptides, as it is known that they reflect the meta- wider than regions with low immunoreactivity. These bolic state of the cell [88]. Given that neuronal MHCI changes were visible not only in layer IV, but also in expression in the visual cortex is activity-regulated, layers I-III and layer VI, which is not surprising since it similar to c-Fos ([15] and this study), this would is known that prolonged deprivation causes responses in enable it to mark or tag neurons or neuronal popula- neurons in all cortical layers [82]. Previous studies in tions that display a distinct activity. A recent study marmosets have shown that such patches correspond to also suggested that neuronal MHCI may be involved in ocular dominance columns. They differ in size in mono- NMDA-induced internalization of AMPARs (a-amino- cularly deprived animals, with wider ODCs receiving 3-hydroxyl-5-methyl-4-isoxazole-propionate receptors, input from the intact eye and showing higher levels of [89]). AMPARs belong to the group of activity- NMDAR1 [61,70]. Interestingly, MHCI-HC protein regulated molecules involved in developmental plasti- detected in this study also localized to NMDAR1-posi- city in the visual cortex [90,91]. As we were able to tive neurons in the cortex of enucleated animals (Addi- reliably detect only the free heavy chain form of MHCI tional file 7), which is also indicative of MHCI proteins on neurons (this study and [56,57]), the sug- association with neuronal activity [61,70]. Therefore, gested link between MHCI and trafficking of AMPARs MHCI-HC immunoreactivity in the visual cortex of enu- is very intriguing considering our current study and cleated animals suggested the upregulation of expression previous studies on MHCI involvement in receptor of this class of genes in neurons receiving input from trafficking [6,56,57]. the intact eye. As mentioned above, synaptogenesis in the marmoset visual cortex peaks in the third postnatal Current limitations month. Although elimination of synapses and synapto- As previously mentioned, there are no true orthologues genesis may occur within the same time window in the between MHC class I genes of rodents and primates developing V1 [83], it is interesting to note that MHCI [17]. MHC gene cluster shows significant interspecies expression peaks during the synaptogenesis stage. More- variability, as well as a fast evolutionary rate [2,3,17]. over, the observed upregulation of MHCI levels in This makes drawing parallels between rodent and pri- response to monocular enucleation points to a possible mate studies extremely difficult. Furthermore, current role in synaptogenesis. policies on the use of non-human primates in research are very limiting, which makes functional studies on Potential interspecies differences in properties of non-human primates hard to perform. neuronal MHCI molecules It is our hope that the further development of trans- The so-called classical MHCI molecules detected in genic marmoset models [77], more flexible research this study are traditionally regarded as having only policies, as well as detailed characterization of the mar- immunity-related functions, but they have recently moset MHC cluster, will provide future researchers with been implicated in synaptic refinement in the visual the tools to investigate the potential functional differ- system [23]. Even though our data indicated a potential ences between neuronal MHCI molecules in rodents interspecies difference in the function of classical and primates in more detail. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 16 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Conclusions horizontal lines in upper panel in (B) indicate areas with high c-Fos Despite the possible interspecies differences in expres- immunoreactivity, while white lines point to low immunoreactivity areas. Scale bar: 0.5 mm. sion of MHCI molecules in the brain, all studies on this Additional file 7: MHCI-HC protein is localized on NMDAR1-positive topic have highlighted yet another important role of neurons in the visual cortex of enucleated animals. MHCI-HC (A) is these molecules. MHC genes have been linked to a present on NMDAR1-positive neurons in the primary visual cortex of number of CNS disorders and the discovery of their enucleated animals (B, white arrowheads in C). Higher magnification reveals MHCI-HC clusters (D) overlapping with NMDAR1 clusters (E, white roles in plasticity processes in the brain has shed new arrowheads in F). Scale bar in C: 50 μm; scale bar in D: 25 μm. light on their etiology [84,92-94]. Further research is Abbreviations: ME, monocularly enucleated animals; V1, primary visual warranted to elucidate the exact mechanisms of action cortex. of the neuronal MHCI genes and the exact identity of Additional file 8: c-Fos mRNA expression is upregulated in response to monocular enucleation. qRT-PCR reveals a significant difference in c- theneuronalMHCIgenepossiblyinvolvedin Fos mRNA expression levels in the whole visual cortices of animals that synaptogenesis. have undergone monocular enucleation (ME) and controls. Data are expressed as mean ± SEM (standard error of the mean) and are representative of three independent experiments performed with Additional material samples isolated from both hemispheres of N = 3 animals/group. Significant differences between groups as determined by Student’s two- Additional file 1: All products of the qRT-PCR reactions yielded a tailed t-test: *, p < 0.05 (t = 2.875 df = 10). single product. After the qRT-PCR reactions, 3-5 μL of one sample for a Additional file 9: Effects of monocular enucleation on the primer pair (Caja-G, c-Fos, GFAP and ACTB) was run on a 2.5% agarose expression of GFAP mRNA and protein expression. A) Enucleation gel. No template controls (NTC) revealed no product. DNA size marker has no significant effect on the levels of GFAP mRNA in the visual (NEB QuickLoad 50 bp) with relevant sizes in bp marked on the left side cortex as determined with qRT-PCR. Abbreviations: ME, monocularly of the gel images. enucleated animals. Data are expressed as mean ± SEM (standard error of the mean) from 2 independent experiments, N = 3 animals/group (ns, Additional file 2: Caja-G qRT-PCR yielded a single product not significant; Student’s two-tailed t-test). B) Enucleation has no corresponding to Caja-G locus only. After the qRT-PCR, the reaction visible effect of GFAP immunoreactivity in the visual cortex of product was purified using QIAquick PCR Purification Kit (QIAGEN) and enucleated animals. Adjacent sections were processed for c-Fos and sequenced using the forward primer used for the qRT-PCR reaction (bold GFAP immunostaining. While c-Fos revealed patchy immunoreactivity in and italics in the Caja-G sequence). The obtained sequence (bolded and the visual cortex of enucleated animals (upper panel), GFAP revealed highlighted in grey in the Caja-G sequence) was identified as Caja-G uniform staining pattern (lower panel). Abbreviations: ME, monocularly (alleles Caja-G*1, *3 and *5) using NCBI BLAST tool. Example of pairwise alignments generated by BLAST, as well as the BLAST hits table are enucleated animals; V1, primary visual cortex. shown in the lower part of the figure. Additional file 3: MHCI-HC protein is localized on both excitatory and inhibitory synapses in the marmoset primary visual cortex. Upper row: MHCI-HC (green; A) partially colocalizes with inhibitory Acknowledgements synapse marker gephyrin (red, B; white arrowheads, C). Lower row: The authors wish to thank T. Meyer-Burhenne and S. Leineweber for expert MHCI-HC (green; D) partially colocalizes with the excitatory synapse animal care and A. Hoffmann, J. Krenzek and A. Heutz for technical marker SAP102 (red, D; white arrowheads, E). Scale bar for all images: 20 assistance. We also wish to thank S. Ferrone for providing the TP25.99 and μm. Q1/28 antibodies, B. Uchanska-Ziegler and C. Rosner for providing the W6/ 32 antibody and N. Yee for critical reading of the manuscript. AR was Additional file 4: MHCI-HC protein is not detected on glial cells in funded by NEUREST MEST-CT-2004-504193 and GGNB/IMPRS Molecular the cortex. Upper panel: vimentin-positive cells and processes (green) Biology Göttingen. in subcortical white matter of the occipital lobes are also GFAP-positive (red; white arrowheads in merged image). Scale bar: 50 μm. Lower Author details panel: MHCI-HC positive cells (green) in subcortical white matter of the Clinical Neurobiology Laboratory, German Primate Center/Leibniz Institute occipital lobes are also GFAP-positive (red; white arrowheads in merged for Primate Research, Kellnerweg 4, Göttingen 37077, Germany. Primate image). Abbreviations: SWM, subcortical white matter; PM1, postnatal Genetics Laboratory, German Primate Center/Leibniz Institute for Primate month 1. Scale bar: 50 μm. A) Upper panel: vimentin immunoreactivity Research, Kellnerweg 4, Göttingen 37077, Germany. Pathology Unit, German cannot be detected in the cortex, as opposed to GFAP-immunoreactivity Primate Center/Leibniz Institute for Primate Research, Kellnerweg 4, (red). Scale bar: 30 μm. Lower panel: In the layer IV of the visual cortex, Göttingen 37077, Germany. Department of Neurology, Medical School, MHCI-HC signal (green) is not overlapping with GFAP-positive astrocytes University of Göttingen, Göttingen, Germany. DFG Research Center (red; merged image). Scale bar: 30 μm. Molecular Physiology of the Brain (CMPB), University of Göttingen, Additional file 5: Microglial MHCI molecules are heterotrimeric. Left Göttingen, Germany. Department of Molecular Biophysics and Biochemistry, panel: Immunohistochemistry with W6/32 antibody specific for the Yale University, 333 Cedar Street, New Haven, CT 06520-8024, USA. heterotrimeric form of MHCI molecules revealed staining of microglial cells (arrows) and processes in the marmoset cortex. Middle panel: Q1/ Authors’ contributions 28 antibody, which recognizes the free heavy chain form of MHCI AR designed and carried out the study, conducted statistical analyses, and molecules, labelled neurons in the same region (arrowheads), similar to drafted the manuscript. CS and KMR performed animal surgeries. GF, LW what can be detected with TP25.99 antibody (right panel, arrowheads). and EF participated in the overall study design and helped draft the Scale bar for all images: 150 μm. manuscript. All authors read and approved the final manuscript. Additional file 6: Primary visual cortex of all enucleated animals reveals banded pattern of MHCI-HC and c-Fos immunoreactivity. Competing interests Black horizontal lines in the lower parts of the images indicate areas with The authors declare that they have no competing interests. high MHCI-HC and c-Fos immunoreactivity; white lines point to low immunoreactivity areas. Animals ME1 and 2 are siblings. 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Behavioral and Brain Functions 2011 7:1. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals http://www.deepdyve.com/lp/springer-journals/activity-dependent-regulation-of-mhc-class-i-expression-in-the-Nji0wKR0qh

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Publisher: Springer Journals
Copyright: Copyright © 2011 by Ribic et al; licensee BioMed Central Ltd.
Subject: Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
eISSN: 1744-9081
DOI: 10.1186/1744-9081-7-1
pmid: 21205317
Publisher site: See Article on Publisher Site

Abstract

Background: Several recent studies have highlighted the important role of immunity-related molecules in synaptic plasticity processes in the developing and adult mammalian brains. It has been suggested that neuronal MHCI (major histocompatibility complex class I) genes play a role in the refinement and pruning of synapses in the developing visual system. As a fast evolutionary rate may generate distinct properties of molecules in different mammalian species, we studied the expression of MHCI molecules in a nonhuman primate, the common marmoset monkey (Callithrix jacchus). Methods and results: Analysis of expression levels of MHCI molecules in the developing visual cortex of the common marmoset monkeys revealed a distinct spatio-temporal pattern. High levels of expression were detected very early in postnatal development, at a stage when synaptogenesis takes place and ocular dominance columns are formed. To determine whether the expression of MHCI molecules is regulated by retinal activity, animals were subjected to monocular enucleation. Levels of MHCI heavy chain subunit transcripts in the visual cortex were found to be elevated in response to monocular enucleation. Furthermore, MHCI heavy chain immunoreactivity revealed a banded pattern in layer IV of the visual cortex in enucleated animals, which was not observed in control animals. This pattern of immunoreactivity indicated that higher expression levels were associated with retinal activity coming from the intact eye. Conclusions: These data demonstrate that, in the nonhuman primate brain, expression of MHCI molecules is regulated by neuronal activity. Moreover, this study extends previous findings by suggesting a role for neuronal MHCI molecules during synaptogenesis in the visual cortex. Background ß-2-microglobulin subunit, and a short peptide compris- The major histocompatibility complex (MHC) is a dense ing 8-15 amino acids that is derived from self or foreign cluster of genes found in all jawed vertebrates that antigens [4,5]. In this form, MHCI modulates immune encodes a great number of proteins involved in immune response by interacting in trans with a large number of responses [1,2]. A group of these genes, MHC class I, immune receptors [6]. Additionally, MHCI heavy chains codes for transmembrane glycoproteins responsible for can be detected under certain conditions on the cell sur- presentation of antigenic peptides to cytotoxic CD8+ T face without ß-2-microglobulin and peptide [6]. It is lymphocytes [3]. MHC class I (MHCI) proteins are typi- thoughtthatinthis “free heavy chain” form, MHCI cally heterotrimers composed of a polymorphic trans- molecules may interact in cis with certain receptors and membrane heavy chain (HC), a noncovalently attached thereby regulate their trafficking [6-8]. Virtually all nucleated cells express MHCI proteins, usually in their heterotrimeric form; however, their expression on neu- * Correspondence: aribic@cnl-dpz.de † Contributed equally rons was always debated [9]. Despite the controversy, Clinical Neurobiology Laboratory, German Primate Center/Leibniz Institute neuronal expression of MHCI under certain conditions for Primate Research, Kellnerweg 4, Göttingen 37077, Germany has been reported [10,11] and recent findings on Full list of author information is available at the end of the article © 2011 Ribic et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 2 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 involvement of neuronal MHCI in brain development elimination, but rather in synaptogenesis. These results and synaptic plasticity were of great surprise [12-15]. not only validate the potentially important role of neuro- These and other studies begun to unravel the previously nal MHCI molecules in visual cortex development, but unknown and complicated mechanisms of interactions also point to interesting interspecies differences in their between the central nervous and the immune system distribution, and potentially their function. that may have great clinical implications [16]. Although MHCI genes are well conserved among Methods mammals, there are a number of differences in the orga- Animals nization, structure, and function of these genes between Thirty-six common male marmoset monkeys (Callithrix rodents and primates, including humans [17]. The first jacchus) were investigated. The animals were obtained study on the function of MHCI molecules in the central from the breeding colony at the German Primate Center nervous system (CNS) proposed a role for them in the (Göttingen, Germany). All investigations and the experi- removal of excess synapses in the developing visual sys- ments were performed to the highest ethical standards tem [15]. The visual system displays two forms of plasti- according to the relevant local, national and interna- city: visual input-driven, activity-dependent plasticity tional regulations concerning the use of animals. All and activity-independent plasticity [18]. The develop- research projects were carried out only with authoriza- ment of the main structures of the visual system, the tion from the relevant ethics committees. We employed thalamus and the primary visual cortex (V1), are at least the minimum number of animals required to obtain at certain developmental stages dependent on the activ- consistent data and to avoid animal suffering. For the ity coming from the retina [19,20]. The thalamic dorso- termination of non-human primates, the legal require- lateral geniculate nucleus (LGN) is the first relay ments, guidelines and recommendations set by the structure of visual input and is organized into segre- national authorities were followed strictly. The use of gated, eye-specific neuronal layers that form upon sti- animals including non-human primates in research in mulation by early spontaneous activity of retinal Germany is based on the “Tierschutzgesetz” (Animal th ganglion cells [19]. Neurons of the LGN send their pro- Protection Law) of the 25 of May, 1998 (BGBl.I Nr.30 jections to V1 where their activity is needed in proper v.29.5.1998, S. 1105) and the EU guidelines 86/609/EEG. development of eye-specific populations of neurons The proposals for research conducted in this study are assembled in the ocular dominance columns (ODCs; approved by the local Government and a specially [18]). Blockade of activity of one eye during develop- appointed Ethical Review Committee (Niedersächsisches ment of the visual circuits while leaving the other one Landesamt für Verbraucherschutz und Lebensmittelsi- intact (monocular deprivation) perturbs the segregation cherheit, permit numbers 33.11.425-04-003/08 and of the LGN neurons into eye-specific layers [19,21]. In 33.11.425-04-026/07). V1, as a consequence of visual deprivation, the popula- For expression studies, animals of the following ages tion of neurons responsive to the intact eye increases were used [25,26]: postnatal days 1 and 7, and postnatal [18,22]. Monocular deprivation by means of tetrodo- months 1, 3, 5, 7, 12, and 21 (N = 3 per age). For mono- toxin-induced block of retinal activity downregulates cular enucleation (ME), the left eyes of one month-old MHCI expression levels in the LGN [15]. Furthermore, marmoset monkeys (N = 6; approximate body weight it was reported that MHCI molecules are indispensable 75 g) were surgically enucleated under general anesthe- for developmental refinement in the LGN, i.e. for sia. As anesthesia, the animals received 0.1 ml of a pre- removal of excess synapses during normal development mix containing 4 mg/ml alphaxalon and 1.33 mg/ml [12,23]. Asides from differences in the structure and alphadolon (Saffan ; Schering-Plough Animal Health, function of MHCI genes, primates and rodents differ Welwyn Garden City, UK), 0.37 mg/ml diazepam, and significantly in terms of structure of their visual systems 0.015 mg/ml glycopyrroniumbromid (Robinul ; Riemser, [24]. To gain an insight into the role of MHCI molecules Germany). Enucleation was carried out as described for in the nonhuman primate brain, we investigated the spa- pet animals [27] and the eyehole was filled with Gelas- tiotemporal pattern of expression of MHCI genes in the typt sponge (Sanofi-Aventis, Frankfurt, Germany) as primary visual cortex of the common marmoset monkey. soon as arterial bleeding was no longer visible. The Our data confirmed that MHCI molecules are expressed wound was closed with an intracutane suture of vicryl in the developing visual cortex of the marmoset monkey 6-0 (V302H; Ethicon, Norderstedt, Germany). Directly and that their levels are regulated by neuronal activity. after surgery (day 0) and at days 3 and 5, all animals However, the temporal pattern of their expression during received an antibiotic (amoxicillin-trihydrate; Duphamox development of the V1 and their expression levels upon LA , Fort Dodge, Würselen, Germany). ME animals and monocular enucleation indicated that MHCI molecules six age-matched controls were sacrificed at five months investigated here may not be involved in synapse of age [28]. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 3 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Brain sections (Promega, Madison, WI, USA) for the antisense and For in situ hybridization, brains were immediately sense probe, respectively, in the presence of 9.25 MBq removed from terminally anesthetized animals [overdose of P-UTP (Hartmann Analytic GmbH, Braunschweig, of ketamine (50 mg/ml), xylazine (10 mg/ml), and atro- Germany; specific activity, 3,000 Ci/mmol) for 1 h at pine (0.1 mg/ml)] and the whole visual cortices were 37°C. Probes were purified using Microspin S-400 HR quickly dissected (area determined according to [29,30]), columns (Amersham Pharmacia, Freiburg, Germany) embedded in Tissue Tek (Sakura Finetek, Heppenheim, and hybridization buffer (50% deionized formamide, 10% Germany), flash frozen in liquid nitrogen, and stored at dextran sulphate, 0.3 M NaCl, 1 mM EDTA, 10 mM -80°C. Frozen brains were sectioned using a cryostat Tris-HCl, pH 8.0, 500 μg/ml tRNA, 0.1 M dithiothreitol, (Leica CM3050, Bensheim, Germany) and coronal sec- and 1 × Denhardt’ssolution) wasadded to yieldafinal tions (10 μm) of whole visual cortices were thaw- probe activity of 5 × 10 cpm. The hybridization mix- mounted on adhesive silane-coated slides (Histobond, ture containing the probe was denatured at 70°C for Marienfeld, Laboratory Glassware, Lauda-Königshofen, 10 min, cooled to 55°C, and pipetted directly onto sec- Germany). For immunohistochemistry, marmosets that tions (80 μl/section). Hybridization was performed for were terminally anesthetized (see above), were perfused 18 h at 68°C. Sections were subsequently washed in 4 × transcardially with 0.9% saline, followed by 200 ml of SSC (0.6 M NaCl, 0.06 M citric acid), 2 × SSC, and 0.5 fixative containing 4% paraformaldehyde in 0.1 M × SSC for 10 min each at 37°C. After incubation (1 h at sodium-phosphate buffer (pH 7.2) for 15 min. The 75°C) in 0.2 × SSC, sections were washed twice in 0.1 × heads were postfixed in the same fixative, and brains SSC, once at 37°C and again at RT, for 10 min each. were carefully removed from the skulls on the following Finally, sections were dehydrated through graded alco- day. After cryoprotection in 0.1 M phosphate-buffered hols, air dried, and exposed to Bio-Max MR film (Amer- saline (PBS; 0.1 mM phosphate buffer, 0.9% NaCl, pH sham Pharmacia) for three days at 4°C. Films were 7.2) containing 30% sucrose, serial coronal sections of developed and fixed with GBX (Kodak, Rochester, NJ, theentirevisualcortices (thickness:40 μmfor expres- USA). sion studies and 60 μm for ME animals and controls) were obtained using a cryostat. Quantitative in situ hybridization After in situ hybridization, sections were coated with PCR cloning of MHCI transcripts photoemulsion (Kodak NBT2, Rochester, NJ, USA) at The isolation of the common marmoset MHC class I 42°C, dried for 90 min at RT, and stored for seven heavy chain cDNA sequences was carried out using weeks at 4°C in a lightproof container. Exposed slides reverse transcriptase polymerase chain reaction (RT- were developed at 15°C for 5 min (Kodak developer D- PCR). One microgram of total brain RNA was reverse 19), rinsed twice briefly in H O, and fixed for 5 min at transcribed using the oligo (dT) primer and 400 U of RT (fixer, Kodak Polymax). Sections were counter- reverse transcriptase (Promega, Mannheim, Germany). stained either with 0.05% toluidine blue in 0.1% diso- An aliquot of this reaction was used as a template in a dium tetraborate (Sigma) for expression studies or with PCR containing primers designed with the Primer3 soft- methyl green (Sigma) for monocular enucleation studies, ware [31]. Primers were devised to amplify full-length cleared in xylol, and coverslipped using mounting med- marmoset MHC class I heavy chain transcripts (acces- ium (Eukitt, Kindler, Freiburg, Germany). Hybridized sion number: U59637). Primer sequences also included sections were visualized with a 40× objective (NA = 1.4; BamHI restriction sites and were as follows: forward 5’- Zeiss) under a light microscope (Axioscope, Zeiss) and CACGGATCCCACTTTACAAGCCGTGAGAGAC-3’, silver grain quantification was performed on a cell-by- reverse 5’-CACGGATCCCTCCTGTTGCTCTCGGG cell basis using ImageJ (U.S. National Institutes of GGCCTTG-3’. Caja-G*1 (accession number: U59637) Health, Bethesda, Maryland, USA). Images were was obtained and cloned into the pDrive vector obtained from layer IV neurons and, for each area (Qiagen). within the primary visual cortex (demarcated according to [29,30]) two images were acquired, i.e., one using a In situ hybridization green filter to eliminate background staining from Cryosections (10 μm) of visual cortices were dried at RT methyl green and one using white light to later precisely for 20 min, fixed in 4% buffered paraformaldehyde localize neuronal nuclei. A circular counting mask of (PFA, pH 7.2), rinsed in PBS, acetylated (0.1 M trietha- 15 μm in diameter was used to delineate the region of nolamine, 0.25% acetic acid anhydride), washed in PBS, interest and was placed over neuronal nuclei during and dehydrated through a graded ethanol series. Caja-G counting. Relative optical density (ROD) threshold plasmid DNA was linearized and riboprobes were intensities were optimized to detect exposed silver synthesized using T7 and SP6 RNA polymerases grains exclusively. The silver grain density within the Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 4 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 region of interest was measured. Grain density was com- asinglePCR product[33].All products were run on pared between layer IV neurons in primary visual cor- 2.5% agarose gels to confirm a single product (Addi- tices of six animals (three slides per animal, minimum tional file 1). The Caja-G PCR product was additionally 300 neurons per animal were counted) using Student’st sequenced using the BigDye Terminator Sequencing Kit test (GraphPad Prism version 4 for Windows, GraphPad (Applied Biosystems) and forward primer in order to Software, San Diego, CA, USA). confirm its identity (Additional File 2). The relative abundance of the MHCI-HC, c-Fos and GFAP mRNA Quantitative RT-PCR transcripts was calculated relative to the mRNA levels of To isolate RNA for RT-PCR, brains were immediately the internal reference gene b-actin and was compared removed from terminally anesthetized animals (see between both left and right cortices of control and enu- above) and whole occipital lobes containing visual cor- cleated animals using Student’s t-test (GraphPad Prism tices were quickly dissected. Total RNA was isolated version 4 for Windows). from both hemispheres of dissected tissue samples from animals at the age of five months (N = 3 controls and N Immunocytochemistry for light microscopy = 3 unilaterally enucleated animals) using the QIAGEN Coronal cryosections (40 μm for expression studies and RNeasy kit (Qiagen, Hilden, Germany) according to the 60 μm for ME animals) of occipital lobes were collected manufacturer’s instructions. As the cortices had to be and washed briefly in PBS before the epitope retrieval separated during RNA isolation due to their size, both step. Epitope retrieval was performed by incubating the left and right hemispheres of all animals were treated as sections for 20 min in 10 mM sodium citrate buffer pre- independent samples. The integrity and quantity of puri- heated to 80°C. Sections were later brought to RT, fied RNA was assessed by spectrophotometry. Comple- washed in PBS, and quenched of endogenous peroxidase mentary DNA (cDNA) was synthesized from mRNA activity using 30 min incubation at RT in 0.5% H O in 2 2 transcripts using oligo (dT) primers and Superscript distilled water. Sections were then washed in PBS, 12-18 II reverse transcriptase (Invitrogen, Karlsruhe, Ger- blocked for 1 h at RT (3% normal horse serum in PBS), many), according to the manufacturer’s instructions. incubated for 16 h at 4°C with mouse monoclonal The Primer3 software v2.0 [31] was used to design TP25.99 or Q1/28 IgG [34,35] kindly provided by S. gene-specific primers, with amplicons ranging from 50 Ferrone, University of Pittsburgh, USA), 1:300 dilution to 150 bp in length. The primers used for the detection in 3% normal horse serum in PBS; monoclonal mouse of MHC class I heavy chain transcripts were: forward 5’- W6/32 [36], 1:300 dilution in 3% normal horse serum in GTGATGTGGAGGAAGAACAGC-3’, reverse 5’-CACT PBS; monoclonal rabbit anti c-Fos (Cell Signalling Tech- TTACAAGCCGTGAGAGA-3’ (CajaG*01, accession nologies, Beverly, MA, USA); monoclonal anti-GFAP number U59637). Primers for the detection of GFAP (Sigma) 1:200 dilution in 0.01% Triton-X 100 and 3% were: forward 5’-AAACGAGTCCCTGGAGAG-3’, normal horse serum in PBS; or control mouse IgG reverse 5’-TCCTGGTACTCCTGCAAGT-3’ (marmoset (Sigma), and washed again. For c-Fos, W6/32 and GFAP GFAP, Ensembl transcript number ENSCJAT00 staining, the epitope retrieval step was not performed. 000024380). Primers for the detection of c-Fos were: Sections were then incubated with biotinylated horse forward 5’-CGAAGGGAAAGGAATAAGAT-3’, reverse anti-mouse IgG or donkey anti-rabbit IgG (Vector 5’-GCAGACTTCTCATCTTCCAG-3’ (marmoset c-Fos, Laboratories, Burlingame, CA, USA), 1:200 dilution in Ensembl transcript number ENSCJAT00000040535). Pri- 3% normal horse serum in PBS, for 1 h at RT. After mers for the detection of b-actin were: forward 5’- washing, sections were incubated with avidin-biotin CATCCGCAAAGACCTGTATG-3’, reverse 5’-GGAG- horseradish peroxidase (Vectastain Elite ABC Kit, Vector CAATGACCTTGATCTTC-3’ (marmoset ß-actin, acces- Laboratories, Burlingame, CA, USA), 1:100 dilution in sion number DD279463). A quantitative analysis of gene 3% normal horse serum in PBS, for 1 h at RT, washed expression was performed using the 7500 Real-time in PBS and then again in 0.05 M Tris/HCl (pH 7.2) PCR apparatus (Applied Biosystems, Darmstadt, Ger- prior to DAB detection (DAB detection with or without many) in combination with Quantitect SYBR green nickel enhancement was performed according to the technology (Qiagen). The light cycler was programmed manufacturer’s instructions; DAB-Kit, Vector Labora- to the following conditions: an initial PCR activation tories). Sections were washed in 0.05 M Tris/HCl (pH step of 10 min at 95°C, followed by 40 cycling steps 7.6) and again in 0.1 M PBS prior to xylol clearance, (denaturation for 15 s at 95°C, annealing for 30 s at 55° dehydration, and coverslipping with Eukitt mounting C, and elongation for 60 s at 72°C). Details of the quan- medium (Kindler). For identification of cortical layers, titative real-time PCR were described previously [32]. sections adjacent to the ones used for immunocyto- Dissociation curves were generated for all PCR products chemistry were stained with toluidine-blue (Sigma). to confirm that SYBR green emission was detected from Digital images of stained sections were acquired using Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 5 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 an Axiophot II microscope (Zeiss). Final images were antibodies) displayed only background fluorescence assembled in Corel PhotoPaint X3 and, in case of higher (data not shown). magnifications, were a composition of 4-5 images along the longitudinal axis of the primary visual cortex Protein extraction [29,30]. Contrast and luminosity were adjusted in Corel Brains were immediately removed from terminally PhotoPaint X3 for images obtained from monocularly anesthetized animals (see above), and the whole visual enucleated animals. cortices were quickly dissected. Whole visual cortex samples were homogenized with a Dounce homogenizer Immunofluorescence and confocal microscopy (tight pestle) in ice-cold homogenization buffer consist- Antibodies used in double-labeling experiments were ing of 50 mM Tris/HCl pH 7.4, 7.5% glycerol, 150 mM applied sequentially and blocking steps were performed NaCl, 1 mM EDTA, 1% Triton-X 100, and complete using normal sera of the host species from which the protease inhibitor cocktail (Roche Diagnostics, Man- respective secondary antibodies were derived. Cryostat nheim, Germany). After homogenization, the samples sections (40 μm) of occipital lobes were rinsed in PBS were centrifuged at 4,000× g for 20 min at 4°C. The before the epitope retrieval step was performed, as resulting supernatant was centrifuged again until it was described above. Nonspecific antibody binding sites clear. Protein concentration was measured using the were blocked with 3% normal serum in PBS for 1 h at Bio-Rad DC Protein assay (Bio-Rad Laboratories, Her- RT. Sections were then incubated with mouse monoclo- cules, CA, USA). nal TP25.99 antibody, 1:300 in 3% normal serum in PBS, for 16 hrs at 4°C, washed, and incubated in sec- Immunoblot analysis ondary antiserum (Alexa 488-coupled goat anti-mouse, Protein preparations were electrophoresed in 12.5% Molecular Probes, Invitrogen, Leiden, Netherlands) at a SDS gels under reducing conditions. Proteins were dilution of 1:500 for 4 h in a lightproof container. Sec- subsequently transferred to nitrocellulose membranes tions were then washed and incubated with either rabbit (Schleicher and Schuell, Dassel, Germany) via semidry anti-MAP2 antibody (1:200, Synaptic Systems, Göttin- electroblotting for 2 h at 1 mA/cm in transfer buffer gen, Germany), rabbit anti-NMDAR1 (1;200, Synaptic containing 25 mM Tris-base, 150 mM glycine, and Systems), rabbit anti-GFAP (1:500, Synaptic Systems), or 10% (v/v) methanol. After the transfer, the blotted rabbit anti-vimentin antibody (1:200, Synaptic Systems) membranes were blocked with 5% (w/v) milk powder in 3% normal serum in PBS for 16 h at 4°C. For GFAP- and 0.1% Tween-20 in PBS for 1 h at RT and were vimentin colocalization studies, the epitope retrieval step then incubated with either monoclonal TP25.99 was not performed and following primary antibodies (1:1,000) or monoclonal anti-SNAP-25 (1:1,000, Synap- were used: rabbit anti-vimentin (1:200, Synaptic Sys- tic Systems) antibodies overnight at 4°C. After washing tems) and mouse anti-GFAP (1:200, Sigma). Sections three times for 5 min in PBS/0.1% Tween-20, blots were then washed and incubated 4 h at RT in secondary were incubated for 1 h at RT with horseradish peroxi- antiserum (Alexa 568-coupled goat anti-rabbit, Molecu- dase-coupled goat anti-mouse IgG (1:4,000, Santa Cruz lar Probes, Invitrogen) diluted 1:500 in 3% normal Biotechnology, Santa Cruz, USA). Prior to visualiza- serum in PBS. Thereafter, sections were washed in PBS tion, blots were washed in PBS/0.1% Tween-20 (3 × and floated/mounted on SuperFrost Plus slides (Men- 5 min) and once more in PBS. Signals were visualized zel-Gläser GmbH, Braunschweig, Germany) in distilled using SuperSignal West Dura enhanced luminescence water, allowed to dry overnight at 4°C, and coverslipped substrate (Pierce Biotechnology, Rockford, IL, USA). with mounting medium (Aqua-Polymount, Polysciences Membranes were subsequently stripped in a mixture of Inc., Warrington, PA, USA). For control sections, the b-mercaptoethanol and SDS in PBS and incubated same procedures were performed omitting the primary with monoclonal anti-b-actin antibody (1:4000, Sigma). antibody. For controls, the same procedures were performed Confocal microscopy was performed using a laser- using the mouse IgG (Sigma) instead of a primary anti- scanning microscope (LSM 5 Pascal, Zeiss) with an body. Control IgG yielded no signals in the Western argon 488 nm laser and a helium/neon 543 nm laser (in blot (data not shown). For quantification, blots were multiple-tracking mode). High magnification, single visualized with MCID Basic software (Imaging optical plane images of layer IV neurons of the primary Research Inc., St. Catherines, Ontario, Canada) so that visual cortex [29,30] or of the subcortical white matter nonsaturating bands were obtained. Quantification was in the occipital lobes were obtained at a resolution of performed using the gel analysis plug-in of ImageJ 1,024 × 1,024 with an Apochromat 63× oil objective (U.S. National Institutes of Health, Bethesda, Mary- (NA = 1.4) and immersion oil (Immersol, Zeiss; refrac- land, USA). Values obtained for MHCI and SNAP-25 tive index = 1.518). The control sections (no primary were normalized to ß-actin values. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 6 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Image analysis of sections from monocularly enucleated animals Digital images of immunostained tissue sections were acquired using an Axiophot II microscope (Zeiss). Images were taken from the V1 areas of right visual cor- tices. Variations in MHCI immunoreactivity through layer IV were measured as described previously [37]. Briefly, images were normalized and black-white inverted using ImageJ (U.S. National Institutes of Health, Bethesda, MD, USA) and regions within layer IV that encompassed the thickness of the entire layer IV (2 mm in length and approximately 1 mm in thickness) were defined as the regions of interest. For identification of cortical layers, sections adjacent to the ones used for immunocytochemistry were stained with toluidine-blue (Sigma). The density profile of layer IV in the primary visual cortex (region demarcated according to [29,30]) was obtained using ImageJ. Values were averaged (using the four closest neighbors) and plotted as a function of the distance along layer IV parallel to the pia mater. After delineating the borders of immunoreactive Figure 1 Lack of MHCI-HC expression in the lateral geniculate patches, their width was measured using ImageJ and nucleus as revealed by in situ hybridization. Autoradiograph of a brain section of a 7 days-old marmoset from the level of the lateral compared using Student’s t-test (GraphPad Prism ver- geniculate nucleus (LGN) processed for in situ hybridization (left) sion 4 for Windows). and toluidine-blue stained section (right). Note the absence of MHCI-HC signals in the LGN (delineated with arrowheads). Results Abbreviations: Dentate gyrus, DG; postnatal day, PD. Scale bar: Expression of MHCI molecules in LGN and V1 of the 1 mm. common marmoset To investigate the expression of MHCI genes in the marmoset LGN and primary visual cortex, a full-length remained the same throughout postnatal months 12 and clone of the heavy chain (HC) of the classical marmoset 21 (data not shown). Emulsion autoradiography revealed MHCI gene Caja-G [accession number U59637 [38]) the presence of silver grains clustered over single cells was used for in situ hybridization experiments. Animals in layer IV of the primary visual cortex (Figure 2B). were chosen based on age and according to the main However, with this technique, the number of labeled stages of visual system development [25,26] and were of cells appeared relatively low because the liquid photo the following ages: postnatal days 1 and 7; and postnatal emulsion that is used for dipping the radiolabeled sec- months 1, 3, 5, 7, 12, and 21. Although LGN develop- tions is less sensitive to the radioactivity than the auto- ment occurs in utero in primates [39,40], we expected radiographic films. The sense probe was used as a to observe strong expression of MHCI-HC (MHCI control and it yielded no signal, thus demonstrating the heavy chain) in newborn animals, as the expression of specificity of the MHCI-HC antisense probe (Figure 2A these genes persists in the LGN of adult rodents and and 2B). cats [12,15].Toour surprise,there wasalmost no Antibodies against marmoset MHCI proteins are not MHCI-HC signal in the marmoset LGN, even after long available; however, because of the high similarity of exposures to autoradiographic films (Figure 1). However, these proteins with their human homologues, we used in situ hybridization revealed a strong expression of the well characterized TP25.99 antibody for the detec- MHCI-HC throughout the visual cortex. On postnatal tion of marmoset MHCI proteins [34,35]. The epitope day 7, this expression was mainly concentrated in layers to which this antibody binds is situated in the a-3 I and IV of both primary and secondary visual cortex domain of MHCI molecules, which is monomorphic [V1 and V2, Figure 2A; regions demarcated according to and the most conserved domain across all species [34]. [29,30]) and in the subcortical white matter (Figure 2A This domain is almost identical between marmosets and and 2B). In older animals (1 to 7 months of age), the humans. Moreover, the TP25.99 antibody is also one of signal became more diffuse, with cells in all cortical theantibodiesthatrecognize thefreeheavychain form layers exhibiting MHCI-HC gene expression (Figure 2A of MHCI [41,42]. TP25.99 recognized a band of and 2B). This pattern of MHCI-HC mRNA expression approximately 45 kDa on Western blots, which is the Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 7 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 2 Expression of MHCI-HC in the primary visual cortex as revealed by in situ hybridization. A) Autoradiographs of visual cortices processed for in situ hybridization. Sections represent the main stages of visual cortex development. The expression of MHCI-HC in the 7 days-old animal (PD7) decreases with progressing age (compare with 7 months-old animal, PM7). Primary visual cortex (V1) is delineated with white dashed lines. Layer IV and subcortical white matter are delineated with white lines. Abbreviations: Postnatal day, PD; postnatal month, PM; primary visual cortex, V1; secondary/prestriate visual cortex, V2; subcortical white matter, SWM; layer IV, IV. Scale bar: 1 mm. B) Upper row: Toluidine-blue stained section of a 7 days-old animal (left) after in situ hybridization, and autoradiograph of the same section (middle panel; film autoradiography) reveal MHCI-HC signals in layers I and IV-VI of the primary visual cortex and in the subcortical white matter (SWM). Emulsion autoradiography (right) reveals silver grains clustered over single cells (arrowheads). Middle row: Toluidine-blue stained section of a 1-month old animal (left) after in situ hybridization and autoradiograph of the same section (middle panel) revealed MHCI-HC signals in all cortical layers and in the subcortical white matter (SWM). Emulsion autoradiography (right) reveals silver grains clustered over single neurons (arrowheads). Bottom row: Sense probe revealed only background signals (left; film autoradiograph) and background levels of silver grains in emulsion autoradiography (right). Roman numerals denote cortical layers. Scale bar for film autoradiographs: 1 mm. Scale bar for emulsion autoradiography: 20 μm. Abbreviations: Postnatal day, PD; postnatal month, PM; primary visual cortex, V1; subcortical white matter, SWM. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 8 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 expected molecular weight of the MHCI-HC (Figure 3A). Protein expression was quantified in animals aged one, three, and five months, which represent the main stages of synaptogenesis, namely the initial, the peak and the refinement stage [26]. MHCI-HC protein levels at these stages coincided with levels of the synaptogen- esis marker SNAP-25 (Figure 3B and [43]). Immunocy- tochemistry revealed a strong MHCI-HC staining of neurons throughout the primary visual cortex of a 7 months-old animal (Figure 4) and the same staining pat- tern was observed in all developmental stages (data not shown). To further demonstrate that MHCI-HC protein expression in the primary visual cortex is neuronal, we performed double-labeling experiments using TP25.99 and an antibody against microtubule associated protein 2 (MAP2), which is an established dendritic marker [44-46]. A punctuate pattern of MHCI-HC immunor- eactivity that colocalized with MAP2-positive neuronal Figure 4 MHCI-HC immunoreactivity in the primary visual cortex of the common marmoset. Representative coronal section of the primary visual cortex of a 7 months-old marmoset probed with TP25.99 antibody (mouse anti-human MHCI) revealing strong staining of neurons in all layers (left). Roman numerals denote cortical layers. Control mouse IgG showed no reaction (right). Scale bar: 200 μm. Abbreviations: Postnatal month, PM; subcortical white matter, SWM; primary visual cortex, V1. processes was observed in the neuronal somata, den- drites and neuropil in the main thalamorecipient layer of V1, layer IV (Figure 5). As previously reported [23], MHCI-HC protein partially colocalized with both gephyrin and SAP102, markers of inhibitory and excita- tory synapses respectively ([47-50]; Additional file 3). In situ hybridization also showed strong MHCI-HC gene expression in the subcortical white matter in the occipi- tal lobes, consistent with previous studies on MHCI in the visual cortex of cats [15]. This region contains spe- cialized glial cells, radial glia, involved in neuronal differentiation and migration [51]. Double-labeling experiments using antibodies against MHCI-HC and Figure 3 MHCI-HC protein levels at different stages of visual vimentin, a marker of radial glia [52,53] confirmed that cortex development. The antibody TP25.99 (mouse anti-human MHCI-HC is indeed expressed on radial glia in the sub- MHCI) recognized bands of appropriate size for MHCI-HC protein cortical white matter (Figure 6). Vimentin-positive cells (MHCI-HC, A) in Western blots of proteins extracted from the also displayed strong immunoreactivity for GFAP (glial marmoset visual cortex. Animals were 1, 3 and 5 months old (PM1, fibrillary acidic protein) in the subcortical white matter 3, 5) representing the main stages of synaptogenesis: initial stage, peak and rapid decline/synaptic refinement, respectively. SNAP-25 ([54]; Additional file 4), but vimentin immunoreactivity was used as a marker of synatogenesis. Data were normalized to ß- could only be detected in this region. No vimentin-posi- actin. Molecular weights (in kDa) are indicated on the left side. Data tive cells and only GFAP immunoreactivity was detected are from three independent experiments with N = 1 animal per in the visual cortex (Additional file 4). The MHCI-HC stage (B). Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 9 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 5 MHCI-HC protein colocalizes with the neuronal marker MAP-2 in layer IV neurons of the V1. MHCI-HC (green; A) is localized mainly to the neuronal somata in the primary visual cortex, where it colocalizes with MAP-2 (red; B and C). Higher magnification of the area indicated by the dashed line in C reveals MHCI clustered over MAP2-positive neurons and processes (arrowheads; D). Scale bar in C: 50 μm; scale bar in D: 25 μm. Abbreviations: postnatal month 7, PM7; primary visual cortex, V1. signal in the V1 did not colocalize with GFAP-positive [56,57], further suggested that neurons might express astrocytes (Additional file 4). However, fully assembled MHC class I molecules preferentially in their free heavy heterotrimeric MHCI molecules could be detected on chain form on the cell surface. Unfortunately, we could microglial cells in the cortex with W6/32 antibody not reliably detect ß-2-microglobulin subunit with the (Additional file 5). W6/32 is a prototypic anti-MHC antibodies available to us (data not shown), although we class I antibody that binds to a conformational epitope have detected ß-2-microglobulin transcripts in the mar- on MHCI heavy chains upon their association with b-2- moset cortex in our previous study [56]. microglubulin and the peptide [36,41,55]. Interestingly, another antibody that recognizes free heavy chains, Expression levels of MHCI molecules are regulated by monoclonal Q1/28 [34] recognized neuronal-like pro- neuronal activity cesses and cell bodies in the marmoset cortex (Addi- Several previous studies suggested a variety of nonim- tional file 5). This, along with our previous studies mune roles for MHCI molecules, most of which refer to Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 10 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 6 MHCI-HC colocalizes with radial glia marker in the subcortical white matter of the occipital lobes.MHCI-HC (green;A) is localized to vimentin-positive radial glia (red; B and C) in the subcortical white matter (SWM). Higher magnification reveals colocalization between MHCI-HC and vimentin signals (white arrowheads in D). Scale bar in C: 50 μm; scale bar in D: 25 μm. Abbreviations: postnatal month 1, PM1; subcortical white matter, SWM. involvement of MHCI free heavy chain form in receptor levels were significantly higher in the visual cortices of trafficking, cell growth and differentiation [7]. As the enucleated animals, as determined by qRT-PCR (quanti- temporal and spatial pattern of MHCI expression corre- tative Real Time Polymerase Chain Reaction, Figure 7). lates with synaptogenesis in the primary visual cortex, Also, quantitative in situ hybridization using the Caja-G we decided to study this further. Enucleation of one eye probe confirmed the qRT-PCR results revealing a higher before critical stages of visual cortex development density of silver grains over cells in layer IV of the pri- induces significant morphological and physiological mary visual cortex of the enucleated animals (Figure 8A changes in V1 [18,22]. Monocular deprivation, induced and 8B). by either unilateral enucleation or by other means (eye-- lid suture or pharmacological blockade of retinal activ- Neurons with higher MHCI-HC expression receive ity), causes the intact eye to dominate the V1, both afferents from the intact eye anatomically and physiologically [18]. Dendritic arbors In situ hybridization was not able to shed light as to of the neurons in V1 receiving afferents from the where the elevated MHCI-HC transcript levels are loca- deprived eye shrink [58]. This shrinkage presumably lized, in neurons receiving afferents from the intact or reduces the width of ODCs subserving the deprived eye from the enucleated eye. Hence, in order to localize [18,58,59]. On the other hand, ODCs subserving the MHCI-HC expression in the V1 of the enucleated ani- intact eye expand [60-63]. It is known that synaptic mals, we performed immunohistochemistry using the input regulates gene expression in target neurons and TP25.99 antibody. Control animals (5 months old) dis- previous gene expression studies have reported major played a relatively uniform staining pattern throughout activity-dependent changes in the expression of numer- V1 (Figure 9A). In contrast, TP25.99 revealed a patchy ous genes [64,65]. We used monocular enucleation pattern of immunoreactivity in V1 of enucleated animals (ME) to induce the aforementioned changes in V1 of (Figure 9Band Additional file 6). To assign the regions the marmoset. Animals were enucleated at one month of high and low immunoreactivity to neurons receiving and were sacrificed at five months of age [28]. MHCI- afferents from either the intact or the enucleated eye, HC gene expression in visual cortices of monocularly we stained adjacent sections for a known activity- enucleated animals and age-matched controls were com- marker, a method commonly employed in monocular pared using qRT-PCR with MHCI-HC PCR primers deprivation paradigms [66,67]. For this study, we used designed to recognize the intracellular domain of Caja- c-Fos as a marker of neuronal activity [68,69]. Expres- G. Both left and right visual cortices were used from all sion of both c-Fos and MHCI-HC was uniform, albeit at animals. In the present study, MHCI-HC transcript a very low level in control animals (Figure 9A and 9B). Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 11 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 7 MHCI-HC mRNA expression is upregulated in response to monocular enucleation. qRT-PCR reveals a significant difference in MHCI-HC mRNA expression levels in the whole visual cortices of animals that have undergone monocular enucleation (ME) and controls. Data are expressed as mean ± SEM (standard error of the mean) and are representative of three independent experiments performed with samples isolated from both hemispheres of N = 3 animals/group. Significant differences between groups as determined by Student’s two-tailed t-test: *, p < 0.05 (t = 2.961 df = 10). However, in animals that had undergone monocular enucleation, column-like patches of c-Fos and MHCI- HC immunoreactivity were visible throughout layer IV of V1 (Figure 9C and 9D and Additional file 6). Com- parison of adjacent sections stained for MHCI-HC and c-Fos showed that the columns with high MHCI-HC immunoreactivity overlap with regions of high c-Fos immunoreactivity (Figure 9C and 9D and Additional file 6). Secondary visual cortex (V2) displayed no such col- umn-like patches, neither in c-Fos nor in MHCI-HC staining (data not shown). Although the patchy appear- ance of MHCI-HC immunoreactivity was encompassing not only layer IV, but also layers II and III, we measured the optical density profiles only in layer IV since this is the main recipient layer. In sections from the enucleated animals, the MHCI-HC optical density profile from the entire layer IV in V1, measured along its horizontal axis (Figure 10A), displayed variations in intensity that were Figure 8 Monocular enucleation upregulates MHCI-HC mRNA not observed in control animals (Figure 10B). Regions in layer IV of the primary visual cortex. A: Numbers of silver grains per cell reveal elevated levels of MHCI-HC expression in layer with high and low immunoreactivity were detected in IV of the V1 of enucleated animals (ME). Data are expressed as these subjects. In contrast, control animals displayed a mean ± SEM (standard error of the mean), N = 3 animals/group. relatively weak and uniform staining of all layers (Figure Significant differences between groups as determined by Student’s 9A; Figure 10B). As it was previously shown that col- two-tailed t-test: *, p < 0.05 (t = 3.781, df = 4). B: Examples of umns with neurons receiving afferents from the intact sections from layer IV of the primary visual cortex of a control and an enucleated animal showing silver grains over cells (circular eye are wider and occupy larger regions in V1, we mea- counting mask). Scale bar: 20 μm. Abbreviations: Postnatal month 5, sured the width of columns exhibiting high and PM5; primary visual cortex, V1. low MHCI-HC immunoreactivity [61]. A significant Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 12 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 9 Primary visual cortex reveals a banded pattern of MHCI-HC and c-Fos immunoreactivity in enucleated animals. A-D: Patches of stained neurons can be observed in enucleated (C and D), but not in control animals (A and B). These patches are detected with the MHCI antibody (C) and with the c-Fos antibody (D). Asterisks in C and D denote identical blood vessels. Roman numerals indicate cortical layers. Abbreviation: primary visual cortex, V1; monocularly enucleated animal, ME. Note: Black horizontal lines in the lower parts of C and D indicate areas with high MHCI-HC and c-Fos immunoreactivity; white lines point to low immunoreactivity areas. difference was found between the widths of columns high expression levels of this gene are associated with exhibiting high and low immunoreactivity, with stronger high neuronal activity. MHCI-HC staining intensity localized in the wider col- umns (Figure 10C). Furthermore, a number of previous Discussion studies have associated the expression of NMDAR1 (N- Several recent studies have implicated MHCI proteins in methyl D-aspartate receptor subunit 1) with develop- the elimination of excess synapses in the visual system mental plasticity in the visual cortex [37,61,70]. After during distinct phases of cortical development monocular deprivation, higherlevelsofNMDAR1are [12,15,23]. MHCI molecules, as well as the organization present on neurons that still receive visual input and of the visual system, differ between rodents and pri- afferents from the intact eye [37,61,70]. In the present mates, including humans [17,24]. We therefore investi- study, MHCI-HC protein was localized on NMDAR1- gated the expression of neuronal MHCI molecules in positive neurons in V1 of enucleated animals, which the brain of the common marmoset monkey. To the further supports the notion that MHCI-HC expression best of our knowledge, the present study is the first to levels are associated with neuronal activity (Additional characterize the spatio-temporal pattern of MHCI gene file 7). Interestingly, transcript levels of the activity mar- expression in the primary visual cortex during postnatal ker c-Fos [68,69] were also significantly elevated in the development in a nonhuman primate. enucleated animals, similar to MHCI-HC levels (Addi- tional file 8). These results confirm the hypothesis that Expression and localization of MHCI molecules in V1 the columns with high MHCI-HC immunoreactivity It is known that virtually all nucleated cells express receive afferents from the intact eye, suggesting that MHCI molecules in form of completely assembled Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 13 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Figure 10 MHCI-HC is upregulated in primary visual cortex neurons that receive afferents from the intact eye. A: Example of the region analyzed for optical density measurements (delineated with white, dashed line). Abbreviations: primary visual cortex, V1; monocularly enucleated animal, ME. B: Optical density profiles recorded from layer IV of the primary visual cortex of a control animal (black dotted line) and two enucleated animals (red and blue dotted lines). C: Width of MHCI-HC immunoreactive column-like patches showing that the wider columns display stronger MHCI-HC staining indicating that MHCI-HC levels are elevated in neurons receiving afferents from the intact eye. Difference between the groups is highly significant as determined by Student’s two tailed t-test: **, p < 0.01 (t = 5.166 df = 4). Data are expressed as mean ± SEM (standard error of the mean), N = 3 animals/group, 12 measurements per animal. Note: Black horizontal lines in (A) and (B) indicate areas with high MHCI-HC immunoreactivity, while white lines point to low immunoreactivity areas. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 14 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 heterotrimers, and in some cases in form of the peptide- situ hybridization that revealed a distinct spatio-tem- free heavy chains [4,6]. The present study clearly poral pattern of MHCI-HC expression, the staining pat- showed that MHCI molecules are expressed on MAP-2 tern generated with the TP25.99 antibody was rather positive neurons of V1. However, in this and our pre- uniform throughout all cortical layers and developmen- vious studies [56,57], we were only able to detect neuro- tal stages. While the MHCI subset-specific riboprobe nal expression of MHCI heavy chain proteins. In used for in situ hybridizationverylikelytargetedonlya addition, in situ hybridization and immunohistochemis- few MHCI genes, the antibody we used for histochem- try revealed high expression levels of MHCI-HC ical detection of MHCI targets the most conserved, throughout the subcortical white matter (SWM) of the monomorphic part of these molecules. Hence, the occipital lobes, consistent with what has previously been TP25.99antibodylikelyrecognized a large number of observed in cats [15]. In SWM, MHCI-HC protein colo- MHCI-HC proteins expressed on V1 neurons, including calized with vimentin-positive radial glial cells. These the ones targeted at the mRNA level by in situ hybridi- highly specialized cells are regarded as neuronal precur- zation riboprobe. As previously mentioned, the common sors and are involved in proper development and migra- marmoset MHCI gene cluster is not yet fully character- tion of cortical neurons [51]. In primates, these cells are ized and so far only two loci have been described, the also GFAP-positive from early prenatal stages, but can classical Caja-G and the non-classical Caja-E [38]. Based be distinguished from astrocytes on the basis of their on this (Additional file 2) and our previous studies distinct morphology and localization [71]. We did not [56,57], we believe that the neuronal MHCI-HC detect any vimentin-positive cells in the cortical layers, detected in the present study is a classical marmoset and MHCI-HC was not expressed in GFAP-positive cor- MHCI, Caja-G. Nonetheless, the levels of MHCI-HC tical astrocytes (Additional file 4), although these astro- protein expression in the visual cortex correlated well cytes were stained with the antibody that recognized with the levels of SNAP-25 (synaptosome-associated fully assembled, heterotrimeric form of MHCI (Addi- protein 25 kDa). This protein is an established synapto- tional file 5). These findings further implicate MHCI in genesis marker [43,75,76] and the present data on proper development of the visual cortex, although their SNAP-25 protein expression levels confirmed previous potential function in this context remains elusive [72]. findings that synapse density in the marmoset V1 As the marmoset MHCI gene cluster is not fully charac- reaches very high values in the third postnatal month, terized yet, we hope that future studies will shed light followed by a rapid decline due to synapse elminiation on the exact identity and potential functional differences [25,26]. Contrary to our expectations and to the pro- between neuronal, radial glial and microglial MHCI. posed role for MHCI in the elimination of synapses Previous studies have shown that MHCI proteins may [12,15,23], MHCI-HC protein expression was at its peak be localized to both pre- and postsynaptic sites already in the third postnatal month, together with [14,23,57,73,74]. The MHCI-HC molecules detected SNAP-25 levels, and was in decline in the fifth postnatal here with confocal microscopy and TP25.99 antibody month. This suggests that, as recently proposed [74], seem to be associated with the postsynaptic sites (cell MHCI proteins may exert their function during synapto- bodies and dendrites, Figure 5) and they displayed no genesis, rather than during refinement and elimination obvious preference for excitatory vs inhibitory synapses of synapses. (Additional file 3), as has previously been reported [23]. MHCI expression in the visual cortex is activity dependent MHCI-HC mRNA and protein expression in the developing As genetic manipulation of primates is still either una- visual cortex vailable or at an early stage [77], we used monocular In contrast to the previous studies in rodents and cats deprivation as an alternative model to further clarify the [12,15], we did not detect expression of MHCI-HC in role of MHCI molecules in the marmoset visual cortex. the LGN at postnatal stages used in this study. It is pos- Prolonged monocular deprivation induced by various sible that MHCI genes are expressed prenatally in the means (in the order of months) induces morphological marmoset LGN, as the segregation of LGN layers in pri- changes in the visual cortex because neurons that mates occurs in utero [39,40]. Furthermore, the probe receive input from the intact eye expand their connec- used here for the detection of MHCI-HC transcripts is tions and cortical space at the expense of neurons that specific for a subset of MHCI molecules, while the receive afferents from the deprived eye [21,60]. A num- probes used in previous studies were mostly pan-specific ber of studies have shown that monocular deprivation and therefore detected a larger variety of MHCI mole- results in the upregulation of growth factors and genes cules [15]. Even so, the present data showed that MHCI associated with neuronal degeneration or synaptogenesis genes are strongly expressed throughout all regions of [64,65,78]. In mice, monocular deprivation increases the visual cortex of the marmoset. In contrast to the in levels of SNAP-25 and SynCAM (synaptic cell adhesion Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 15 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 molecule) transcripts [78], both of which are required MHCI in the visual system, the very large number of for synaptogenesis [79-81]. Interestingly, MHCI-HC these genes and the fact that there are no true ortholo- transcript levels detected in the present study after gues between rodents and primates [17] makes direct monocular enucleation with qRT-PCR and in situ hybri- comparisons very difficult. On the other hand, the pos- dization for classical marmoset MHCI-HC were also sible interspecies differences in function are not sur- higher in response to monocular enucleation. The levels prising. MHCI molecules exhibit a multitude of of neuronal activity marker c-Fos were also elevated. On functions and may, for example, transmit both activat- the contrary, GFAP displayed no significant change in ing and inhibitory signals in the immune system [7,84]. either expression levels or in expression pattern in enu- MHCI proteins are also necessary for immunological cleated animals (Additional file 9). This even further synapse formation [85]. In addition to their role in correlated MHCI-HC levels with neuronal activity, and synaptic refinement and stripping, MHCI molecules not with microglial activation. have been implicated in stabilization of certain types of We used immunohistochemistry to localize the ele- terminals in the peripheral nervous system of mice vated MHCI-HC levels to neurons receiving afferent [86]. The exact mechanism and role of MHCI in the inputs from the intact eye. In V1 of enucleated animals, visual cortex is yet to be elucidated, although previous both the well-established activity marker c-Fos [68,69] studies have shown that MHCI may associate with PI- and MHCI-HC immunostaining revealed a pattern of 3, which is known to be a synaptogenic molecule column-like patches, where regions of high c-Fos and [8,87]. Another possibility includes the MHCI-present- high MHCI-HC immunoreactivity overlapped and were ing peptides, as it is known that they reflect the meta- wider than regions with low immunoreactivity. These bolic state of the cell [88]. Given that neuronal MHCI changes were visible not only in layer IV, but also in expression in the visual cortex is activity-regulated, layers I-III and layer VI, which is not surprising since it similar to c-Fos ([15] and this study), this would is known that prolonged deprivation causes responses in enable it to mark or tag neurons or neuronal popula- neurons in all cortical layers [82]. Previous studies in tions that display a distinct activity. A recent study marmosets have shown that such patches correspond to also suggested that neuronal MHCI may be involved in ocular dominance columns. They differ in size in mono- NMDA-induced internalization of AMPARs (a-amino- cularly deprived animals, with wider ODCs receiving 3-hydroxyl-5-methyl-4-isoxazole-propionate receptors, input from the intact eye and showing higher levels of [89]). AMPARs belong to the group of activity- NMDAR1 [61,70]. Interestingly, MHCI-HC protein regulated molecules involved in developmental plasti- detected in this study also localized to NMDAR1-posi- city in the visual cortex [90,91]. As we were able to tive neurons in the cortex of enucleated animals (Addi- reliably detect only the free heavy chain form of MHCI tional file 7), which is also indicative of MHCI proteins on neurons (this study and [56,57]), the sug- association with neuronal activity [61,70]. Therefore, gested link between MHCI and trafficking of AMPARs MHCI-HC immunoreactivity in the visual cortex of enu- is very intriguing considering our current study and cleated animals suggested the upregulation of expression previous studies on MHCI involvement in receptor of this class of genes in neurons receiving input from trafficking [6,56,57]. the intact eye. As mentioned above, synaptogenesis in the marmoset visual cortex peaks in the third postnatal Current limitations month. Although elimination of synapses and synapto- As previously mentioned, there are no true orthologues genesis may occur within the same time window in the between MHC class I genes of rodents and primates developing V1 [83], it is interesting to note that MHCI [17]. MHC gene cluster shows significant interspecies expression peaks during the synaptogenesis stage. More- variability, as well as a fast evolutionary rate [2,3,17]. over, the observed upregulation of MHCI levels in This makes drawing parallels between rodent and pri- response to monocular enucleation points to a possible mate studies extremely difficult. Furthermore, current role in synaptogenesis. policies on the use of non-human primates in research are very limiting, which makes functional studies on Potential interspecies differences in properties of non-human primates hard to perform. neuronal MHCI molecules It is our hope that the further development of trans- The so-called classical MHCI molecules detected in genic marmoset models [77], more flexible research this study are traditionally regarded as having only policies, as well as detailed characterization of the mar- immunity-related functions, but they have recently moset MHC cluster, will provide future researchers with been implicated in synaptic refinement in the visual the tools to investigate the potential functional differ- system [23]. Even though our data indicated a potential ences between neuronal MHCI molecules in rodents interspecies difference in the function of classical and primates in more detail. Ribic et al. Behavioral and Brain Functions 2011, 7:1 Page 16 of 18 http://www.behavioralandbrainfunctions.com/content/7/1/1 Conclusions horizontal lines in upper panel in (B) indicate areas with high c-Fos Despite the possible interspecies differences in expres- immunoreactivity, while white lines point to low immunoreactivity areas. Scale bar: 0.5 mm. sion of MHCI molecules in the brain, all studies on this Additional file 7: MHCI-HC protein is localized on NMDAR1-positive topic have highlighted yet another important role of neurons in the visual cortex of enucleated animals. MHCI-HC (A) is these molecules. MHC genes have been linked to a present on NMDAR1-positive neurons in the primary visual cortex of number of CNS disorders and the discovery of their enucleated animals (B, white arrowheads in C). Higher magnification reveals MHCI-HC clusters (D) overlapping with NMDAR1 clusters (E, white roles in plasticity processes in the brain has shed new arrowheads in F). Scale bar in C: 50 μm; scale bar in D: 25 μm. light on their etiology [84,92-94]. Further research is Abbreviations: ME, monocularly enucleated animals; V1, primary visual warranted to elucidate the exact mechanisms of action cortex. of the neuronal MHCI genes and the exact identity of Additional file 8: c-Fos mRNA expression is upregulated in response to monocular enucleation. qRT-PCR reveals a significant difference in c- theneuronalMHCIgenepossiblyinvolvedin Fos mRNA expression levels in the whole visual cortices of animals that synaptogenesis. have undergone monocular enucleation (ME) and controls. Data are expressed as mean ± SEM (standard error of the mean) and are representative of three independent experiments performed with Additional material samples isolated from both hemispheres of N = 3 animals/group. Significant differences between groups as determined by Student’s two- Additional file 1: All products of the qRT-PCR reactions yielded a tailed t-test: *, p < 0.05 (t = 2.875 df = 10). single product. After the qRT-PCR reactions, 3-5 μL of one sample for a Additional file 9: Effects of monocular enucleation on the primer pair (Caja-G, c-Fos, GFAP and ACTB) was run on a 2.5% agarose expression of GFAP mRNA and protein expression. A) Enucleation gel. No template controls (NTC) revealed no product. DNA size marker has no significant effect on the levels of GFAP mRNA in the visual (NEB QuickLoad 50 bp) with relevant sizes in bp marked on the left side cortex as determined with qRT-PCR. Abbreviations: ME, monocularly of the gel images. enucleated animals. Data are expressed as mean ± SEM (standard error of the mean) from 2 independent experiments, N = 3 animals/group (ns, Additional file 2: Caja-G qRT-PCR yielded a single product not significant; Student’s two-tailed t-test). B) Enucleation has no corresponding to Caja-G locus only. After the qRT-PCR, the reaction visible effect of GFAP immunoreactivity in the visual cortex of product was purified using QIAquick PCR Purification Kit (QIAGEN) and enucleated animals. Adjacent sections were processed for c-Fos and sequenced using the forward primer used for the qRT-PCR reaction (bold GFAP immunostaining. While c-Fos revealed patchy immunoreactivity in and italics in the Caja-G sequence). The obtained sequence (bolded and the visual cortex of enucleated animals (upper panel), GFAP revealed highlighted in grey in the Caja-G sequence) was identified as Caja-G uniform staining pattern (lower panel). Abbreviations: ME, monocularly (alleles Caja-G*1, *3 and *5) using NCBI BLAST tool. Example of pairwise alignments generated by BLAST, as well as the BLAST hits table are enucleated animals; V1, primary visual cortex. shown in the lower part of the figure. Additional file 3: MHCI-HC protein is localized on both excitatory and inhibitory synapses in the marmoset primary visual cortex. Upper row: MHCI-HC (green; A) partially colocalizes with inhibitory Acknowledgements synapse marker gephyrin (red, B; white arrowheads, C). Lower row: The authors wish to thank T. Meyer-Burhenne and S. Leineweber for expert MHCI-HC (green; D) partially colocalizes with the excitatory synapse animal care and A. Hoffmann, J. Krenzek and A. Heutz for technical marker SAP102 (red, D; white arrowheads, E). Scale bar for all images: 20 assistance. We also wish to thank S. Ferrone for providing the TP25.99 and μm. Q1/28 antibodies, B. Uchanska-Ziegler and C. Rosner for providing the W6/ 32 antibody and N. Yee for critical reading of the manuscript. AR was Additional file 4: MHCI-HC protein is not detected on glial cells in funded by NEUREST MEST-CT-2004-504193 and GGNB/IMPRS Molecular the cortex. Upper panel: vimentin-positive cells and processes (green) Biology Göttingen. in subcortical white matter of the occipital lobes are also GFAP-positive (red; white arrowheads in merged image). Scale bar: 50 μm. Lower Author details panel: MHCI-HC positive cells (green) in subcortical white matter of the Clinical Neurobiology Laboratory, German Primate Center/Leibniz Institute occipital lobes are also GFAP-positive (red; white arrowheads in merged for Primate Research, Kellnerweg 4, Göttingen 37077, Germany. Primate image). Abbreviations: SWM, subcortical white matter; PM1, postnatal Genetics Laboratory, German Primate Center/Leibniz Institute for Primate month 1. Scale bar: 50 μm. A) Upper panel: vimentin immunoreactivity Research, Kellnerweg 4, Göttingen 37077, Germany. Pathology Unit, German cannot be detected in the cortex, as opposed to GFAP-immunoreactivity Primate Center/Leibniz Institute for Primate Research, Kellnerweg 4, (red). Scale bar: 30 μm. Lower panel: In the layer IV of the visual cortex, Göttingen 37077, Germany. Department of Neurology, Medical School, MHCI-HC signal (green) is not overlapping with GFAP-positive astrocytes University of Göttingen, Göttingen, Germany. DFG Research Center (red; merged image). Scale bar: 30 μm. Molecular Physiology of the Brain (CMPB), University of Göttingen, Additional file 5: Microglial MHCI molecules are heterotrimeric. Left Göttingen, Germany. Department of Molecular Biophysics and Biochemistry, panel: Immunohistochemistry with W6/32 antibody specific for the Yale University, 333 Cedar Street, New Haven, CT 06520-8024, USA. heterotrimeric form of MHCI molecules revealed staining of microglial cells (arrows) and processes in the marmoset cortex. Middle panel: Q1/ Authors’ contributions 28 antibody, which recognizes the free heavy chain form of MHCI AR designed and carried out the study, conducted statistical analyses, and molecules, labelled neurons in the same region (arrowheads), similar to drafted the manuscript. CS and KMR performed animal surgeries. GF, LW what can be detected with TP25.99 antibody (right panel, arrowheads). and EF participated in the overall study design and helped draft the Scale bar for all images: 150 μm. manuscript. All authors read and approved the final manuscript. Additional file 6: Primary visual cortex of all enucleated animals reveals banded pattern of MHCI-HC and c-Fos immunoreactivity. Competing interests Black horizontal lines in the lower parts of the images indicate areas with The authors declare that they have no competing interests. high MHCI-HC and c-Fos immunoreactivity; white lines point to low immunoreactivity areas. Animals ME1 and 2 are siblings. 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Activity-dependent regulation of MHC class I expression in the developing primary visual cortex of the common marmoset monkey

Activity-dependent regulation of MHC class I expression in the developing primary visual cortex of the common marmoset monkey

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Activity-dependent regulation of MHC class I expression in the developing primary visual cortex of the common marmoset monkey

Activity-dependent regulation of MHC class I expression in the developing primary visual cortex of the common marmoset monkey

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