A role for Sv2c in basal ganglia functions

Abstract

SV2C is an isoform of the synaptic vesicle 2 protein family that exhibits a particular pattern of brain expression with enriched expression in several basal ganglia nuclei. In the present study, we have investigated SV2C implication in both normal and pathological basal ganglia functioning with a peculiar attention to dopamine neuron containing regions. In SV2C-/- mice, the expression of tyrosine hydroxylase mRNA in midbrain dopaminergic neurons was largely and significantly increased and enkephalin mRNA expression was significantly decreased in the caudate-putamen and accumbens nucleus. The expression of SV2C was studied in two models of dopaminergic denervation (6-OHDA- and MPTP-induced lesions). In dopamine-depleted animals, SV2C mRNA expression was significant increased in the striatum. In order to further understand the role of SV2C, we performed behavioral experiments on SV2C-/- mice and on knock-down mice receiving an injection of adeno-associated virus expressing SV2C miRNA specifically in the ventral midbrain. These modifications of SV2C expression had little or no impact on behavior in open field and elevated plus maze. However, even if complete loss of SV2C had no impact on conditioned place preference induced by cocaine, the specific knock-down of SV2C expression in the dopaminergic neurons completely abolished the development of a CPP while the reaction to an acute drug injection remains similar in these mice compared to control mice. These results showed that SV2C, a poorly functionally characterized protein is strongly involved in normal operation of the basal ganglia network and could be also involved in system adaptation in basal ganglia pathological conditions.

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

“…Similar findings were made in mice with TLE resulting from electrical stimulation of basolateral amygdala followed by self-sustained SE, where selective SV2C overexpression was seen in the CA4 and CA3 hippocampal (stratum lucidum) areas [71]. Interestingly, SV2C mRNA expression was also significantly increased in the striatum of animals challenged with 6-hydroxydopamine, a model of Parkinson’s disease [72]. Together, these data indicate that SV2C may be involved in presynaptic remodeling in response to neuronal hyperexcitability or cellular stress conditions.…”

Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease

“…SV2 proteins appear to promote vesicular function in various ways, perhaps in part by stabilizing transmitter content in the vesicle through neurotransmitter interaction with the protein's heavily glycosylated intraluminal loop (32,33) or by coordinating vesicular mobilization (24,25,44,45) or by interacting with synaptotagmin-1 to facilitate calciumstimulated exocytosis (26-30, 46, 47). Though only SV2A has been strongly implicated in epilepsy, recent evidence has hinted at a potential link between SV2C, dopamine and PD (37,48,49). Our neurochemical data directly indicate that SV2C plays a particularly important role in the dopaminergic nigrostriatal pathway.…”

Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease

“…SV2 proteins appear to promote vesicular function in various ways: by coordinating vesicular mobilization (26, 33), by interacting with synaptotagmin-1 to facilitate calcium-stimulated exocytosis (22, 27, 28, 31, 32, 34), or perhaps by stabilizing intravesicular transmitters (30, 35) [although functional evidence has not supported this last hypothesis (23, 24, 27)]. Although only SV2A has been strongly implicated in epilepsy, recent evidence has hinted at a potential link between SV2C, dopamine, and PD (40, 41, 47). Our neurochemical data directly indicate that SV2C plays a particularly important role in the dopaminergic nigrostriatal pathway.…”