The synaptic vesicle glycoprotein 2C modulates dopamine release in the ventral striatum and contributes to behaviors associated with reward Público
Stout, Kristen Ann (2016)
Abstract
The synaptic vesicle is a critical nexus for regulated neurotransmitter release and a number of proteins precisely orchestrate its filling, trafficking, fusion, and endocytosis. Every synaptic vesicle contains the synaptic vesicle glycoprotein 2 (SV2). Three isoforms of SV2 exist: SV2A, B, and C. SV2A and SV2B are expressed ubiquitously through the central nervous system and contribute to normal neurotransmission. SV2C expression is restricted to the basal ganglia, labeling 70% of dopamine neurons. Additionally, SV2C is strongly expressed in the ventral pallidum, the main output of the nucleus accumbens. The contribution of SV2C to the synaptic vesicle cycle has not been well established. I hypothesized that SV2C modulates dopamine release and contributes to behaviors associated with reward. To test this hypothesis, I first optimized voltammetric recording of dopamine release in the ventral pallidum of wildtype mice and demonstrated that it is correlated with reward behavior. I used this technique, in combination with established protocols, to assess reduced dopamine release in the ventral striatum and pallidum of SV2C knockout (SV2C-KO) animals generated in our lab. I interrogated SV2C mechanism using stimulus train depletion and radioactive vesicular uptake. Behavioral metrics support the observed neurochemical deficits; SV2C-KO animals have increased methamphetamine-stimulated locomotor activity and reduced conditioned place preference compared with controls. Interestingly, female mice express 40% more SV2C and show increased reduction in dopamine release and reward behavior than male mice. Given its discrete expression, importance in dopamine neurotransmission, and contribution to reward behavior, SV2C is a promising target for further interrogation towards the development of novel therapeutics for addiction treatment.
Table of Contents
Abstract 2
Acknowledgements 4
List of figures 7
Chapter 1 - introduction: rationale, hypothesis, and scope 9
Chapter 2 - the synaptic vesicle glycoprotein 2: structure, function, and disease relevance 14
Structure 15
Expression 15
Function 17
Sv2s in neurological disease 24
Conclusions 32
Chapter 3 - selective enhancement of dopamine release in the ventral pallidum of methamphetamine-sensitized mice 37
Abstract 38
Introduction 39
Results and discussion 42
Materials & methods 52
Chapter 4 - genetic ablation of synaptic vesicle glycoprotein 2c (sv2c) reduces dopamine neurotransmission and alters methamphetamine-induced behavior 77
Abstract 78
Introduction 79
Methods 80
Results 85
Discussion 91
Chapter 5 - future directions - sex differences dictate behavioral reduction of meth effect in sv2c-ko animals 115
Introduction 116
Methods 117
Results 121
Discussion 123
Chapter 6 - Concluding remarks 135
References 139
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