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/lp/springer-journals/gpa-14-a-g-i-subunit-mediates-dopaminergic-behavioral-plasticity-in-c-CLf3w4pNVe
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- Springer Journals
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- Copyright © 2013 by Mersha et al.; licensee BioMed Central Ltd.
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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- 1744-9081
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- 10.1186/1744-9081-9-16
- pmid
- 23607404
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Abstract
Background: Precise levels of specific neurotransmitters are required for appropriate neuronal functioning. The neurotransmitter dopamine is implicated in modulating behaviors, such as cognition, reward and memory. In the nematode Caenorhabditis elegans, the release of dopamine during behavioral plasticity is in part modulated through an acid-sensing ion channel expressed in its eight dopaminergic neurons. A D2-like C. elegans dopamine receptor DOP-2 co-expresses along with a Gα subunit (GPA-14) in the anterior deirid (ADE) pair of dopaminergic neurons. Findings: In follow-up experiments to our recently reported in vitro physical interaction between DOP-2 and GPA-14, we have behaviorally characterized worms carrying deletion mutations in gpa-14 and/or dop-2. We found both mutants to display behavioral abnormalities in habituation as well as associative learning, and exogenous supply of dopamine was able to revert the observed behavioral deficits. The behavioral phenotypes of dop-2 and gpa-14 loss-of-function mutants were found to be remarkably similar, and we did not observe any cumulative defects in their double mutants. Conclusion: Our results provide genetic and phenotypic support to our earlier in vitro results where we had shown that the DOP-2 dopamine receptor and the GPA-14 Gα subunit physically interact with each other. Results from behavioral experiments presented here together with our previous in-vitro work suggests that the DOP-2 functions as a dopamine auto-receptor to modulate two types of learning, anterior touch habituation and chemosensory associative conditioning, through a G-protein complex that comprises GPA-14 as its Gα subunit. Keywords: C. elegans, Learning, Habituation, Memory, gpa-14, dop-2, Dopamine, Dopamine receptor, G-protein, Gα Findings [5]. Dopamine released into the synaptic cleft by pre- Neural plasticity is dependent upon various neurotrans- synaptic neurons interacts with its receptors after which it mitters, including the catecholamine dopamine [1,2] and is either degraded by monoamine oxidase or taken up abnormal dopaminergic transmission is associated with through a dopamine transporter [6]. The release of dopa- memory disorders [3]. Dopamine receptive neurons have mine from acidic vesicles is accompanied by increase in dopamine receptors mainly localized to the morphologic- H ion concentrations stimulating presynaptic acid- ally plastic dendritic spine regions [4]. In humans, these sensing ion channels (ASICs) that are proposed to modu- seven-transmembrane G-protein coupled dopamine re- late levels of dopamine in the synaptic cleft [7,8]. Some ceptors are classified into D1- and D2-types. Activated mammalian D2-receptors are localized to dopamine re- D1-type receptors couple to Gα and activate adenylyl cy- leasing neurons in a pre-synaptic configuration and clase, and D2-receptors tend to act antagonistically to D1- thereby act as auto-receptors [9]. receptors, mediating the signal transduction through Gα Caenorhabditis elegans is an ideal invertebrate model to study genes involved in behavioral plasticity [10-12]. In the adult hermaphrodite C. elegans, dopamine is * Correspondence: hsdhillon@desu.edu Equal contributors synthesized in eight neurons: two anterior deirid neurons Department of Biological Sciences, Delaware State University, Dover, (ADEs), two posterior deirid neurons (PDEs) and four DE 19901, USA cephalic neurons (CEPs) [13]. Four dopamine receptor Full list of author information is available at the end of the article © 2013 Mersha 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. Mersha et al. Behavioral and Brain Functions 2013, 9:16 Page 2 of 7 http://www.behavioralandbrainfunctions.com/content/9/1/16 genes have been identified in the C. elegans genome: backwards [22]. The mechanical stimulus was repeated dop-1, dop-2, dop-3 and dop-4. Based on pharmacological with 10 sec intervals until the animal no longer properties of their protein products and their sequence responded to the stimulus. In order to confirm that the profiles, DOP-1 is classified as a D1-type receptor, while novel anterior touch based assay used here was in fact DOP-2 and DOP-3 are classified as D2-type receptors measuring habituation, we initially provided 20 gentle and DOP-4 is invertebrate specific [14]. Loss-of-function anterior touches (with 10 sec inter-stimulus intervals) to mutants for dop-1 tend to habituate faster [15,16] and each worm and their response was scored after each loss-of-function dop-2 mutants display associative learning stimulus as 1 or 0 (1 = worm moves away, and 0 = no re- deficits [8]. DOP-3 and DOP-4 have both been implicated sponse or worm continues moving in same direction). We in response to aversive soluble repellents [17,18]. Seven- observed that increasing number of touches decreased the transmembrane receptors such as the dopamine receptors probability of the worms’ response and we did not observe typically transduce their signal through G-proteins. The C. abrupt disruption in their ability to respond (Figure 1A). elegans genome encodes for 21 Gα,2Gβ and 2 Gγ genes; The latter would have indicated sensory fatigue. We also one particular gene, gpa-14, codes for a Gα subunit and plotted the same data in terms of the average point at shows expression overlap with DOP-2 as well as with which worms stopped responding to the anterior touch ASIC-1 in the ADE dopaminergic neurons [8,19,20]. stimulus (Figure 1B). Based on assay similarities and sub- We have recently reported physical interaction between stantial neural circuitry overlap of the observed behavior DOP-2 and GPA-14 and that the third intracellular loop with the extensively studied mechanical tap habituation, of DOP-2 is essential for binding to GPA-14 in vitro we consider that a decrease in response to anterior touch [21]. To study the functional significance of the above is a form of habituation, although additional tests will allow molecular interaction in the intact organism, results necessary verification [22,23]. Our subsequent assays from follow-up behavioral and genetic experiments are recorded the number of mechanical stimuli repeated with presented here. 10 second intervals until the response failed as a measure of habituation of individual worms. The results are Hypothesis noteable in that both dop-2(vs105) and gpa-14(pk247) mu- Considering the role of dopamine in plasticity and the tants exhibited significantly faster habituation rates com- interaction of DOP-2 with GPA-14, we hypothesized that pared to wild-type (Figures 1A and B, 2A). deletion of gpa-14 will cause behavioral abnormalities It has been previously reported that dop-2(vs105) mutants similar to dop-2 mutants [8,21]. Towards this end, we are deficient in chemotaxis based associative learning para- report that both dop-2(vs105) and gpa-14(pk347) loss- digms [9]. We tested the performance of gpa-14(pk347) in of-function mutants display associative learning deficits as a learning assay in which the chemo-attractant isoamyl al- well as faster habituation at remarkably similar rates. cohol (IAA) was paired with starvation [9]. For condition- Additionally, the phenotype of the gpa-14(pk347);dop-2 ing, the animals were exposed to 3 μlof IAA for 90 (vs105) double mutant is virtually identical to either minutes. IAA (2μl) diluted to 1/100 in ethanol was applied single-mutant, and exogenous dopamine tends to revert to the gradient spot and ethanol (2μl) was applied to the di- the mutant behavior. luent point, and worms were placed equidistant to the two points. Plates were left undisturbed for one hour, after gpa-14 and dop-2 mutants display similar behavioral deficits which the animals were counted to calculate a chemotaxis We carried out a behavioral profiles for gpa-14(pk347) and index for each plate [9,24]. Naive worms showed strong dop-2(vs105) mutants obtained through the Caenorhabditis attraction towards to 1:100 dilution of IAA. After condi- Genetic Center, and cultured on standard nematode growth tioning, N2 worms displayed significantly reduced attrac- media with E. coli OP50 at 20°C. Compared to wild type tion to isoamyl alcohol compared to both gpa-14(pk347) N2 animals, individuals of both strains are phenotypically and dop-2(vs105) (Figure 3A). Additionally, there was no normal in terms of body size, shape, growth, movement significant difference between the learning capacity of the and locomotion and they respond normally to gentle touch, gpa-14(pk347) or the dop-2(vs105) strains. Similar asso- ciative learning results were obtained using paradigms and display normal chemotaxis to both soluble and volatile chemicals. Dopamine has been reported to mediate move- that used non-volatile sodium chloride as uncondi- ment and food sensing behaviors in that when C. elegans tioned stimulus (Additional file 2). In control experi- ments we did not observe any decrease in attraction to encounter food, they move more slowly [2]. Our basal slowing assays did not reveal any significant difference be- isoamyl alcohol when the animals had been previously ex- tween wild type animals and the deletion mutants (Add- posed to isoamyl alcohol in the presence of food/E. coli, confirming that the decrease in response observed upon itional file 1). A modified habituation assay was used in which a forward moving worm was gently touched on the conditioning in the absence of E. coli is a learned response anterior with an eyelash hair causing the worm to move and not due to adaptation [Figure 3C]. Mersha et al. Behavioral and Brain Functions 2013, 9:16 Page 3 of 7 http://www.behavioralandbrainfunctions.com/content/9/1/16 N2 0.9 dop-2 (vs 105) 0.8 gpa-14 (pk347) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 1 2 3 4 5 6 7 8 9 1011121314151617181920 Number of Touches ** Figure 1 Habituation measure based on response failure after repeated gentle anterior touch. (A) 20 gentle anterior touches each separated by 10 second inter-stimulus interval were given and the response for each touch was scored as 1 if thw worm responded by moving away, and 0 if there was no response or worm continued moving in same direction. The probability of the worms responding to the touch decreased with increasing number of stimuli. (B) The raw data used in Figure-1A was plotted as a bar graph to illustrate that the average habituation point of dop-2(vs105) and gpa-14(pk347) deletion mutants was significantly lower than WT animals (p < 0.05, two tailed student’st-test, n = 30 for each strain). Error bars represent SEM values. In order to test whether DOP-2 and GPA-14 exert their correlated with slower habituation rates [16,17]. Behavioral influence on the observed adaptive behavior through deficits attributed to low levels of dopamine have been the same pathway, a gpa-14(pk347);dop-2(vs105) double ameliorated by providing exogenous dopamine [8,15,16]. mutant was generated. This double mutant adapted Upon assaying in the presence of 5mM exogenous significantly faster than N2 at rates similar to those dopamine, we were able to bring habituation rates of observed for gpa-14(pk347) or dop-2(vs105) single mutants both the single-mutants [gpa-14(pk347) and dop-2 (Figure 2A). No cumulative abnormalities were observed (vs105)] as well as the double mutant [gpa-14(pk347); in the double mutant indicating a genetic interaction dop-2(vs105)] to levels similar to the habituation rate between dop-2 and gpa-14. of wild type N2 animals (Figure 2B). Addition of ex- ogenous dopamine was also able to rescue the condi- tioned associative learning deficits for the gpa-14 Dopamine supplements revert behavioral deficits in (pk347) and dop-2(vs105) deletionsaswellas the mutants gpa-14(pk347);dop-2(vs105) double deletion mutants It has been shown that dopamine deficiency results in faster (Figure 3B). habituation rates while abundance in dopamine has been Response Probablity Number of Touches Mersha et al. Behavioral and Brain Functions 2013, 9:16 Page 4 of 7 http://www.behavioralandbrainfunctions.com/content/9/1/16 ns Figure 2 Deletion mutants in gpa-14 and dop-2 habituate faster than WT, and are lowered to WT levels by exogenous dopamine. Nematode Growth Media (NGM) plates were prepared fresh the night before the assay and left overnight at room temperature. Before the assay, 10 young adult worms were transferred to the NGM plates without food. Worms were gently touched on the anterior with an eyelash hair every 10 seconds until habituated. In response to this stimulus, the worms typically move backwards. The number of times the animal moved backward until it no longer responds to the stimulus was counted. The experiment was repeated by adding 60 μl of 5 mM dopamine spread on the 90 mm plates and allowed to dry for 10 minutes. (A) Both gpa-14(pk347) and dop-2(vs105) mutants habituate faster than wild type (N2) animals. (p < 0.05, Student’s two-tailed t-test, n = 55). (B) After the application of exogenous dopamine, the habituation rates of the mutants reverted back to the wild type rates. (p = 0.37 Student’s two-tailed t-test, n = 40; error bars represent SEM values). The habituation rate of the gpa-14(pk347);dop-2(vs105) double mutant is not significantly different to either single mutant when tested in the absence (p = 0.18, Student’s two-tailed T-test) or presence of dopamine (p = 0.43, Student’s two-tailed t-test). Discussion receptor) has been proposed previously [16]. It will be in- We provide genetic and phenotypic support to our previ- teresting to explore whether DOP-1 and DOP-2 work as ously reported in vitro interaction between the DOP-2 an antagonistically coordinating pair as indicated by the dopamine receptor and the GPA-14 Gα subunit [21]. The pharmacological properties of D1- and D2- receptor types gpa-14(pk347) and dop-2(vs105) mutants display faster [5]. Supplementary exogenous dopamine in either of rates of habituation and diminished associative learning the single mutant or the double mutant used in this capacities. Faster mechanosensitive habituation has been study reverted the observed phenotypic abnormalities, in- reported for mutants in dop-1, which codes for a D1-like dicating that DOP-2 and GPA-14 play an upstream role receptor [15], and crosstalk between AVM touch neurons in regulating the dopaminergic pathway of behavioral (which express a D1-like receptor, DOP-1) and ADE plasticity in worms. In addition to its role in learning dopaminergic neurons (which express the D2-like DOP-2 and memory, dopamine has been reported to regulate Number of Touches Number of Touches Mersha et al. Behavioral and Brain Functions 2013, 9:16 Page 5 of 7 http://www.behavioralandbrainfunctions.com/content/9/1/16 0.7 0.6 0.5 0.4 Naïve 0.3 Conditioned 0.2 0.1 ns 0.7 0.6 0.5 0.4 Naïve 0.3 Conditioned (5mM DA) 0.2 0.1 0.7 Naïve 0.6 Conditioning in the presence of food 0.5 0.4 0.3 0.2 0.1 Figure 3 Deletion mutants in gpa-14 and dop-2 display limited associative learning that is rescued by exogenous dopamine. Associative learning chemotaxis assay. Three-day-old synchronized worms were conditioned with 3 μl of isoamyl alcohol on freshly prepared chemotaxis plates and tested with 1:100 isoamyl alcohol in the absence of food, as described previously [8,24]. Plates were left undisturbed for one hour and then kept at −10°C for 3 minutes. Chemotaxis index was calculated by subtracting the number of worms at the diluent sector from the number of worms at the chemical gradient sector and dividing by the total number of worms on the plate. Tests were then repeated in the presence of plates supplemented with 60 μl of 5 mM exogenous dopamine. (A) While naïve strains [wild type, dop-2(vs105) and gpa-14(pk347)] are equally attracted to isoamyl alcohol but after conditioning, wild type worms display significantly greater decrease in attraction towards isoamyl alcohol than dop-2(vs105) and gpa-14(pk347) (p = 0.35 for naive and p < 0.05 for conditioned animals, ANOVA). Additionally, the conditioned response of the gpa-14;dop-2 double mutant is the same as either single mutant (p = 0.46, One-Way ANOVA). (B) When conditioned in the presence of exogenous dopamine, no statistical significance was noted between the wild types and the mutants (p = 0.65 for naives and p = 0.88 for conditioned, One Way ANOVA). (C) As a control, 3-day-old synchronized worms were exposed to 3 μl of isoamyl alcohol in the presence of E. coli for 90 minutes and tested for their attraction to 1:100 isoamyl alcohol. No significant difference in attraction was observed for wild type or either of the mutants [dop-2(vs105) and gpa-14(pk347)] before or after treatment (p = 0.85 for naives and p = 0.89, One Way ANOVA). Bars represent SEM values n ≥ 3 assays for each strain. Chemotaxis Index Chemotaxis Index Chemotaxis Index Mersha et al. Behavioral and Brain Functions 2013, 9:16 Page 6 of 7 http://www.behavioralandbrainfunctions.com/content/9/1/16 food encounter response of C. elegans [2]. According to Additional files our results, the deletion of dop-2 or gpa-14 has no effect Additional file 1: Basal slowing rates for dop-2(vs105) and gpa-14 on their food encounter response. This could imply that, (pk347) mutants do not differ from wild type animals. Body bends of although dopamine activity is reduced in these mutants, 3 day old individual worms were counted for 20 seconds. Basal slowing its reduction may not be significant enough to affect their assay with food is represented by the white bars while basal slowing assay without food is represented by the grey bars. Each bar indicates food encounter response. Another possibility is that basal the average body bends/20 seconds in three experiments. Error bars slowing may not be as sensitive to dopamine levels as indicate SEM (n = 60 for each strain; P = 0.067 without food and P = 0.178 mechanosensation and chemosensensation. with food). Absence of any additional or cumulative abnormalities in Additional file 2: gpa-14(pk347) deletion mutants displayed associative learning deficits when paired with either soluble or the gpa-14(pk347);dop-2(vs105) double mutant provides volatile chemicals, isoamyl alcohol or sodium chloride, respectively. genetic support towards an interaction between dop-2 and n = 90 in three experiments; *: P < 0.001; ns: non-significant; unpaired t-test. gpa-14 and that their protein products participate in the Additional file 3: A model for the molecular interactions same molecular pathway during behavior plasticity. Appar- modulating neurotransmitter levels at a C. elegans dopaminergic synapse {modified from [8]}. Release of dopamine can activate auto- ently, the observed habituation and associative learning be- receptor function of DOP-2 to initiate signal transduction through GPA-14 haviors in both mutants [gpa-14(pk347) and dop-2(vs105)] ([21], and this report). In parallel, the accompanying drop in synaptic pH due may give an impression of contradictory phenotypes. to the release of H ions from the acidified vesicles activates acid sensing cation channels (ASIC). Stimulation of DOP-2 and activation of ASIC call While diminished associative learning clearly correlates allow two molecular loops in the presynaptic neuron so as to modulate with poorer neuronal summation, faster habituation levels of dopamine in the synaptic cleft. These two pathways are likely to does not necessarily draw a parallel with an antagon- crosstalk through relay molecule/s that remain unknown as yet. istic explanation. On the other hand faster habitu- ation may correlate with ignoring a cue earlier than Abbreviations optimum assuming that WT habituation represents an gpa-14: Gene for G-protein alpha subunit-14; GPA-14: Protein product coded by gpa-14; dop-2: Gene for D2 like dopamine receptor; DOP-2: dop-2 protein product; optimal rate. In summary, examining the behavioral pro- ASIC: Acid sensing ion channel; asic-1: Gene for a subunit of C. elegans ASIC. file of dop-2(vs105) and gpa-14(pk347) deletion mutants has revealed that both show similar aberrations in plasti- Competing interests city, and our results with the dop-2;gpa-14 double mutant The authors declare that they have no competing interests. indicate that GPA-14 and DOP-2 work together in the Authors’ contributions same pathway. In order to rule out the contribution of Conceived project: NT, SH. Designed experiments: MM, RF, PP, SH. Performed background mutations, follow-up experiments using experiments: MM, RF, RM. Wrote manuscript: NT, SH. All authors have read RNAi knockdowns or transgenic rescue of the mutants and approve the final manuscript. can provide required validation of the results presented Acknowledgement here. Thanks to Drs. Geraldine Seydoux, Jeff Rosen, Len Davis, Melissa Harrington These results are significant in that neuroimaging and anonymous reviewers for valuable suggestions and comments, CGC for studies in humans indicate that deficient feedback providing C. elegans strains (supported by the NIH Office of Research Infrastructure Programs grant P40 OD010440). Funding to the lab by NIH is monitoring in the cortex is associated with learning gratefully acknowledged (NIGMS-COBRE 1P20GM103653 - 01A1). deficits due to D2 receptor polymorphisms [25,26]. The ASIC and DAT-1 pathways are also known to Author details Department of Biological Sciences, Delaware State University, Dover, modulate dopamine release in the dopaminergic neu- DE 19901, USA. Institute of Molecular Biology and Biotechnology, rons including ADEs and have been proposed to work Foundation for Research and Technology-Hellas, Medical School, University in conjunction with DOP-2 ([8] and Additional file 3). of Crete, Heraklion, Crete 70013, Greece. However, the nature of the upstream or parallel role of Received: 13 June 2012 Accepted: 12 April 2013 DOP-2 in the plasticity pathway is not understood at the Published: 22 April 2013 molecular level. It is conceivable that DOP-2 may act as an auto-receptor in the ADE neurons and upon stimula- References tion it transduces the extracellular dopamine signal 1. Kandel ER: The molecular biology of memory storage: a dialog between genes and synapses. Biosci Rep 2001, 21(5):565–611. through the GPA-14 Gα subunit [8,21]. Alternately, 2. 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Jocham G, Klein TA, Neumann J, Cramon DY, Reuter M, Ullsperger M: Submit your next manuscript to BioMed Central Dopamine DRD2 polymorphism alters reversal learning and associated and take full advantage of: neural activity. J Neurosci 2009, 29(12):3695–3704. 27. Jomphe C, Tiberi M, Trudeau LE: Expression of D2 receptor isoforms in cultured neurons reveals equipotent autoreceptor function. • Convenient online submission Neuropharmacol 2006, 50(5):595–605. • Thorough peer review • No space constraints or color figure charges doi:10.1186/1744-9081-9-16 Cite this article as: Mersha et al.: GPA-14, a Gα subunit mediates i • Immediate publication on acceptance dopaminergic behavioral plasticity in C. elegans. Behavioral and Brain • Inclusion in PubMed, CAS, Scopus and Google Scholar Functions 2013 9:16. • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit
Journal
Behavioral and Brain Functions – Springer Journals
Published: Apr 22, 2013