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Background: Olfaction is often affected in parkinsonian patients, but dopaminergic cells in the olfactory bulb are not affected by some Parkinson-inducing drugs. We investigated whether the drug MPTP produces the olfactory deficits typical of Parkinson and affects the olfactory bulb in mice. Findings: Lesioned and control mice were tested for olfactory search, for motor and exploratory behavior. Brains and olfactory mucosa were investigated via immunohistochemistry for thyrosine hydroxylase, Olfactory Marker Protein and cyclic AMP-dependent protein kinase as an intracellular pathway involved in dopaminergic neurotransmission. MPTP induced motor impairment, but no deficit in olfactory search. Thyrosine hydroxylase did not differ in olfac- tory bulb, while a strong decrease was detected in substantia nigra and tegmentum of MPTP mice. Olfactory Marker Protein decreased in the olfactory bulb of MPTP mice, while a cyclic AMP-dependent protein kinase increased in the inner granular layer of MPTP mice. Conclusions: MPTP mice do not present behavioural deficits in olfactory search, yet immunoreactivity reveals modifications in the olfactory bulb, and suggests changes in intracellular signal processing, possibly linked to neuron survival after MPTP. Keywords: Parkinson’s disease, Animal models, Olfactory bulb, Protein kinase A dopamine release [6, 7]. Moreover, in olfactory neurons Background dopamine inhibits adenylyl cyclase  and in OB gran- In human Parkinson’s disease (PD) patients, an impair- ule cells activation of D1 receptors modulates GABA A ment in the sense of smell and in olfactory structures is receptors through the cAMP/protein kinase A (PKA) often reported [1, 2]. Neurons of the olfactory system activation . are affected by degenerative changes, like the presence of Dopamine and cAMP signalling pathway mutu- Lewy bodies [3, 4] at an early stage, when motor deficits ally interact also in brain nuclei involved in PD. PKA are not yet apparent: hence, modifications of the olfac - stimulates dopamine uptake , and activates tyros- tory system can be used for early PD diagnosis . ine hydroxylase (TH) . On striatal GABAergic neu- Olfactory processing is linked to dopaminergic sign- rons, D1 receptor activates PKA, that phosphorylates aling, which has a prominent role in the olfactory bulb glutamate NMDA receptors . PKA regulates dopa- (OB) circuitry: dopamine D2 receptors in terminals of mine physiology and modulates the activity of proteins olfactory neurons and in dendrites of mitral/tufted cells involved in PD, including LRRK2, alpha-synuclein, tau modulate glutamate release, and in terminals of GABAe- and TH [13–16]. rgic/dopaminergic cells they modulate GABA and The OB is one of the main dopaminergic nuclei in the brain . It receives axons from new receptors that con- *Correspondence: firstname.lastname@example.org tinuously differentiate in the olfactory neuroepithelium, Department of Molecular Medicine, University of Padova, Via Marzolo, 3, and new cells from the subventricular zone, that become 35131 Padua, Italy Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mucignat and Caretta Behav Brain Funct (2017) 13:1 Page 2 of 7 periglomerular and granular cells. Dopamine is a parac- collected before treatment were compared to those col- rine signal for differentiation of subventricular stem cells lected after injection: data were analyzed with mixed , therefore a deficit in dopaminergic cells acts also on design analysis of variance (ANOVA, factors Group: con- neuron turnover in the OB . Moreover, cAMP regu- trol/MPTP; Day: pre- vs. post-treatment) and post hoc lates differentiation and survival of new neurons in the Newman–Keuls, using Statistica 5 software (www.stat- OB . soft.com). The significant level was p < 0.05. Data from To better understand whether mesencephalic and OB behavioral tests are presented as mean ± SEM. dopaminergic neurons respond differentially to chemical insults, we investigated the changes in TH and PKA in the Immunohistochemistry OB of the murine PD MPTP (1-methyl-4-phenyl,1,2,3,6- Three or 5 days after injection, mice were euthanized tetrahydropyridine) model. (Tanax 20 mg/kg, i.p.). After preincubation of paraffin- embedded sections for 1 h with 2% bovine serum albu- Methods min, nose and brain sections were incubated overnight Animals and treatment with Olfactory Marker Protein (OMP) antibody (Wako, Experiments were authorized according to the directive Neuss, Germany, 1:600); brains were also incubated with 86/609/EEC. Twelve C57BL/6j male mice 4 months old TH (Santa Cruz Biotechnology, Heidelberg, Germany, were used (Charles River, Lecco, Italy). MPTP hydrochlo- 1:100), or synaptophysin antibodies (Sigma, Milan, ride (Sigma, Milan, Italy; 15 mg/kg in 0.9% NaCl, n = 6) Italy, 1:100). Frozen sections were washed for 30 min or saline solution (0.9% NaCl, n = 6) was i.p. injected, in 2% Triton-X100, fixed for 1 min in formalin at 37 °C four times every 2 h. and incubated overnight with anti- murine PKA RIIal- pha (Santa Cruz Biotechnology, Heidelberg, Germany, Behavioral tests 1:200); adjacent sections were incubated with 100 nM Mice were weighted, evaluated for neurologic deficits 8-thioacetamido-fluorescein-cAMP (SAF-cAMP) to vis - and tested 5 days before and five after injections. On the ualize PKA RI . Secondary antibodies (Sigma, Milan, day of injections, tests started 1 h after the last injection. Italy; or Molecular Probes, Milan, Italy) 1:400 were incu- The open field test measures locomotion and bated 1 h at 37 °C. Slides were evaluated independently exploration. The mouse was introduced in a cage with a Leica microscope (objectives: 20×, 40×, 100×) (55 × 33 × 20 cm) for 10 min and videotaped. A software by two observers on a semiquantitative 5-step scale. (Smart 2.5, 2B Biological Instruments, Varese, Italy) cal- Unaltered images obtained using the same conditions culated distance, resting time, and number of rearings on were mounted with Corel Draw 12 (Corel Corporation, the walls . Thigmotaxis was quantified by measuring Ottawa, Canada). the permanence time and the time spent resting in prox- imity of the walls, excluding a central area (35 × 16 cm). Results The pole test detects bradykinesia : the mouse Behavioral tests was placed on the top of a pole (1.5 cm diameter, 50 cm Mice did not differ in body weight, before and after height). The time until it reached the floor was recorded the treatment: before treatment, 25.1 ± 1.1 versus (maximum 3 min). 24.9 ± 1.1 g for controls and MPTP-treated, respectively; The grip test  consisted in placing forepaws on the after treatment: 24.2 ± 1.1 versus 24.4 ± 1.2 g for con- middle of a wire, 2 mm × 90 cm, 15 cm above the floor: trols and MPTP-treated, respectively. the time to fall down or to reach the lateral platforms was All mice during the first and second repetition of the recorded (maximum 3 min). tests improved their performance, to reach a steady- The cookie-finding test evaluates olfactory function state performance before the treatment (Fig. 1). After . On the second day pre-injection and after injection, the treatment, MPTP-treated mice displayed some defi - mice were overnight deprived of food then put in a cage cits, in comparison to controls and to their pre-treatment (42 × 25 × 15 cm) with a food pellet buried under the scores. sawdust: the latency to discover it was recorded within The Cookie-finding test did not differ between controls 5 min. The test was repeated after 1 h with a pellet in a and MPTP mice when food was hidden. Only the fac- visible position to control for motivation to eat. The test tor Day was significant, F(1,10) = 6.995, p < 0.05: both was not repeated every day in order to avoid unnecessary groups after treatment were slower in retrieving hidden stress due to overnight food restriction. food, possibly as a consequence of the stress imposed by The tests were repeated on all mice up to day 3 post- injections. MPTP mice did not display any obvious deficit injection, then half of the mice were sacrificed, on day with visible food. All mice were able to retrieve the food 4 and 5 three mice were tested in each group. The data in both invisible and visible conditions. Mucignat and Caretta Behav Brain Funct (2017) 13:1 Page 3 of 7 Fig. 1 Time course of behavioral performance in different tests. Control mice (times symbol) and MPTP mice (filled triangle) mean ± SEM were compared between groups on day 5 (last day before treatment) and day 6 (after treatment). The vertical line indicates the time of injections, asterisk indicates that both groups were different from the pre-treatment, hash symbol indicates that MPTP mice differ from controls after treatment. a Cookie-finding test, with the food pellet hidden. b Cookie-finding test with the food pellet in a visible position. c Open field test, distance travelled. d Number of rearings on the walls during the open field test. e Cumulative time spent resting in the open field test. f Time to reach the ground in the pole test. g Grip test, time to reach effectively the extremity. h Grip test, time to fall down A reduction in motor activity after MPTP was appar- in the number of rearings; the significant interaction ent in the open field, with a decrease in the distance Group × Day, F(1,10) = 7.817 p < 0.05, showed that only travelled [Group: F(1,10) = 20.094, p < 0.005 controls: MPTP mice performed less rearings after the treatment, 3136.9 ± 214.8 cm, MPTP: 1776.4 ± 214.3 cm] and 28.6 ± 5.4 and 36.8 ± 6.4 rearings for controls (p = 0.25), Mucignat and Caretta Behav Brain Funct (2017) 13:1 Page 4 of 7 and 21.8 ± 5.6 versus 3.0 ± 1.8 rearings in MPTP mice Table 1 OMP and TH immunostaining (p < 0.005). The resting time differed between groups, Control Day 3 Day 5 F(1,10) = 22.834, p < 0.001, with MPTP mice resting for OMP a longer time compared to controls, 550.0 ± 7.6 versus Olfactory nerve +++ + + 497.2 ± 7.9 s. Olfactory glomeruli +++ + + By analysing only to the zone adjacent to the walls, the TH factor Day was different, F(1,10) = 71.838, p < 0.00001: Olfactory bulb ++ ++ ++ both control and MPTP mice spent a longer time (includ- Substantia nigra +++ ± ± ing walking and resting) along the walls after the treat- ment, compared to the day before treatment (p < 0.005). No labeling (−); faint labeling (±); moderate labeling (+); intense labeling (++); very intense labeling (+++) This may be due to the stress of injections. Considering only the time spent resting in the proximity of the walls, both the factors and the interaction were significant. The interaction Group × Day, F(1,10) = 9.952 p < 0.02, (Fig. 2e, f ). This difference was not present in the acces - showed that while controls did not vary (360.2 ± 16.3 sory OB. Synaptophysin did not change in both control vs. 387.8 ± 17.5 s, respectively), MPTP mice spent a and MPTP mice. longer time resting along the border after the treatment No obvious modification was apparent in PKA RI, yet (386.6 ± 16.9 vs. 522.5 ± 29.6 s before and after the treat- 3 days after MPTP PKA RII was brighter in the inner ment respectively, p < 0.001). granular layer of the main OB and in the granule cells of In the pole test, the factor Day was significant, the accessory OB, compared to controls (Fig. 2g, h, see F(1,10) = 13.673, p < 0.005, and the interaction tended to also ). Five days after MPTP, this difference was less significance, F(1,10) = 4.749, p = 0.054: only MPTP mice apparent, the most intense granule cells were confined were slower in reaching the ground after the treatment immediately below the mitral cell layer, while the inner (7.3 ± 2.7 vs. 62.1 ± 12.2 s), while controls did not vary granular layer was very faint. significantly (11.8 ± 7.0 vs. 26.0 ± 9.0 s). In the grip test, the time to reach one end was dif- Discussion ferent: the significant interaction, F(1,10) = 12.597 Multiple factors contribute to the onset and progress of PD, p < 0.01, showed that only MPTP mice took longer to that initially targets few susceptible neuron types in motor reach the extremity after the treatment (24.1 ± 6.7 vs. nuclei of glossopharyngeal and vagus nerves, and in the 156.6 ± 23.3 s in MPTP mice, p < 0.001, and in controls: anterior olfactory nucleus [2, 3, 24]. Many animal models 25.5 ± 5.7 vs. 49.8 ± 20.5 s). Only mice treated with are available for mimicking PD landmarks, however none MPTP fell down (5 out of 6 mice), as shown by the inter- can reproduce in full the human pathology. The picture is action Group × Day, F(1,10) = 24.217, p < 0.001. even more complicated by the presence of both motor and non-motor symptoms, whose assessment in animal models Immunohistochemistry may be difficult and need careful overall interpretation (for Data on immunohistochemistry are summarized in a review, see ). We choose the MPTP model because Table 1 and representative sections are shown in Fig. 2. As we were interested in olfactory dysfunctions, which are a expected, TH was reduced in substantia nigra after MPTP hallmark of early PD stages. MPTP administered acutely in (Fig. 2a, b), but did not change in the OB (Fig. 2c, d). mice can reproduce early stages of PD , however, it is In the nose of both groups, OMP labelling was promi- not sufficient for fully exploring PD, since MPTP-injected nent in olfactory neurons, olfactory fila, and vomerona - mice recover spontaneously, which precludes the study of sal neurons. However, the olfactory nerve and glomeruli pharmacological interventions. Moreover, various strains in the main OB were consistently fainter in MPTP mice of mice show different sensitivity to MPTP. (See figure on next page.) Fig. 2 Immunohistochemistry on horizontal brain sections. Bar 200 μm for a, b, e, f; 50 μm for c, d, g, h. a–d TH immunolabelling. a Substan- tia nigra/ventral tegmental area appear labelled in a control mouse; caudal on the right. ip interpeduncular nucleus, sn substantia nigra, sum supramammillary nucleus, vta ventral tegmental area. b The same area is almost unlabelled in a MPTP mouse, 3 days after injections; rostral on the right. c, d Periglomerular cells are similarly labelled in a control mouse (c) and in a MPTP-treated mouse (d), 3 days after injections; caudal on top right. e, f OMP immunoreactivity in the olfactory bulb of a control (e) and a MPTP mouse (f), 3 days after injections. In the control mouse, the olfactory nerve and glomerular layer are labelled; also the accessory olfactory bulb glomerular layer is labelled. Caudal on the lower right. g, h RII immunoreactivity in the main olfactory bulb of a control (g) and a MPTP-treated mouse, 3 days after injections. Caudal on the top, lateral on the left. m mitral cell layer, ig inner granular layer Mucignat and Caretta Behav Brain Funct (2017) 13:1 Page 5 of 7 Mucignat and Caretta Behav Brain Funct (2017) 13:1 Page 6 of 7 PD implies a complex imbalance of the dopaminergic an exaggerated increase in TH . Moreover, glu- system. However, not all dopaminergic neurons in the tamatergic corticostriatal pathway is overactive after brain are equally affected by degeneration. nigrostriatal denervation, and subsequently striatal PKA- Here, in MPTP mice olfactory search behavioural dependent NMDA phosphorylation increases . performance is normal, yet some modifications can be Striatal deafferentation increases neurogenesis in the detected via immunoreactivity in the OB. olfactory bulb, mostly for new dopaminergic cells [40, MPTP in mice induces both behavioral and neuro- 41]. In our MPTP mice, the PKA transient increase in chemical changes that mimic human PD: altering free OB inner granular layer, which hosts also the developing radicals quenching and reducing TH and dopamine new neurons coming from the subventricular zone, sug- transporter in the substantia nigra and striatum  gests an upregulation of the cAMP-mediated signalling result in motor impairments, bradykinesia and catalepsy in response to MPTP, which should be studied in greater . However, MPTP does not worsen olfaction in both detail. humans and mice [28, 29]. In our experiment, mice were The differential effects of MPTP in OB neurons were impaired in motor performance, as shown by short trav- related to the lack of the dopamine transporter, which elled distance and less rearings on the walls—an increase uptakes the toxic MPTP metabolite, making OB neu- in the rearings is used as an index of anxiety. However, rons MPTP-resistant . While further studies, includ- MPTP mice performed similarly to controls in olfac- ing other animal PD models like 6-OHDA, are needed, tory retrieving, which also included motor performance. the present data confirm that TH immunoreactivity is This may be due to differential involvement of the moti - not affected in the OB after MPTP injection. However, vational system, which is conceivably more activated in we challenge the idea that the olfactory system is not discovering and reaching food items. PD patients are affected by MPTP at all, since a decrease in OMP and a impaired in the motor but also in cognitive/integra- transient increase in PKA RII were consistently observed, tive levels of motor control , and often show apathy suggesting a specific response to MPTP in OB neurons, and indecisiveness : similarly, our mice move under that is not apparent in the nigra, and could be exploited a sufficiently strong drive. However, their good perfor - for therapeutic purposes. mance in the cookie-finding test does not imply a normal olfactory function. This test involves exposure to above- Abbreviations threshold stimuli: it is possible that MPTP mice show ANOVA: analysis of variance; GABA: gamma-aminobutirric acid; MPTP: subtler olfactory deficits. Noteworthy in a genetic PD 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OB: olfactory bulb; OMP: Olfac- tory Marker Protein; PBS: phosphate buffered saline; PD: Parkinson’s disease; model, mice were able to detect and habituate to odors, PKA: cAMP-dependent protein kinase; R: regulatory subunit of PKA; SAF-cAMP: but showed deficits in more stringent olfactory tests . 8-thioacetamido-fluorescein-cAMP; TH: tyrosine hydroxylase. MPTP modifies the expression of several proteins: Authors’ contributions in the striatum it reduces dopamine, TH, dopamine Conceived project, designed and performed experiments: CM and AC. Wrote transporter, vesicle monoamine transporter and alpha- manuscript: CM. Both authors read and approved the final manuscript. synuclein, while monoaminooxidase A and B and cat- Author details echol-O-methyl-transferase remain unchanged . Department of Molecular Medicine, University of Padova, Via Marzolo, 3, Reduced TH levels were apparent in our MPTP mice in 2 35131 Padua, Italy. INBB, National Insitute of Biostructures and Biosystems, the brainstem dopaminergic nuclei. Rome, Italy. Department of Pharmacy, University of Parma, Parma, Italy. The dopaminergic pathway is linked to cAMP intracel - Acknowledgements lular signalling in both brainstem and olfactory system: We thank Michela Bondì for data collection and Marco Redaelli for video TH is induced by the cAMP-mediated signalling path- analysis. way . In PD substantia nigra, both D1 receptors and Competing interests DARPP32 appear downregulated . Dopaminergic The authors declare that they have no competing interests. neurons are protected against MPTP toxicity after the Availability of data and materials inhibition of monoaminooxydase-B, which acts via PKA All data generated or analysed during this study are included in this . Moreover, substantia nigra is protected from MPTP manuscript. by phosphodiesterase inhibitors, that enhance cAMP Ethics approval and consent to participate and subsequently PKA . Here, the transient increase The experiments were authorized according to the directive 86/609/EEC and in OB PKA after MPTP may be linked to a protective approved by the Italian Ministry of Health and by the University of Padova response in these neurons, opening a new challenge for ethical committee. neuroprotection in other brain areas. 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Behavioral and Brain Functions – Springer Journals
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