The synaptic vesicle glycoprotein 2C modulates dopamine release in the ventral striatum and contributes to behaviors associated with reward Open Access

Stout, Kristen Ann (2016)

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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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