Role of SNARE Interactions in Central Synapse Function

描述（由申请人提供）：在中枢突触中，小突触蛋白2（syb 2，也称为VAMP 2）是主要的突触囊泡SNARE（可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体）蛋白，其与质膜SNARE SNAP-25和突触融合蛋白1相互作用以执行胞吐作用。然而，虽然缺乏syb 2的神经元几乎完全没有诱发的神经传递，但它们仍然保持着显著水平的自发神经递质释放。syb 2基因缺失后这种残留的自发释放的生理作用仍然是难以捉摸的。最近的研究表明，替代囊泡陷阱蛋白，如VAMP 4，VAMP 7（也称为破伤风不敏感或TI-VAMP）和Vps 10 p尾相互作用因子1a（Vti 1a）功能上与syb 2不同，并独立地进行自发和一些异步神经递质释放。这些研究表明，这些替代囊泡SNARE构成独立功能的突触囊泡群体的分子标签，并提供了一个潜在的分子基础，选择性调节不同形式的神经递质释放。在这个应用程序中，我们建议检查这些替代SNARE介导的神经递质释放形式的生理影响。我们将描述这些替代SNARE介导的神经递质释放如何通过三个特定目的指导神经元信号传导和突触功效。在第一个目标，突触缩放引起的自发神经递质释放的选择性操纵将被检查。第二个目标将集中在自发神经递质释放引起的突触后Ca 2+信号。最后，第三个目标将探讨在一个完整的突触回路中通过选择性操纵自发神经递质释放来调节突触可塑性。总的来说，这些互补的实验将阐明自发神经传递如何调节生理网络中的神经元功能。从这些研究中获得的信息将提供新的见解突触基板，可能会受到一些神经精神和神经系统疾病，包括重度抑郁症，自闭症和精神分裂症。

DESCRIPTION (provided by applicant): In central synapses, synaptobrevin2 (syb2, also called VAMP2) is the predominant synaptic vesicle SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein that interacts with the plasma membrane SNAREs SNAP-25 and syntaxin1 to execute exocytosis. However, while neurons lacking syb2 have a nearly complete absence of evoked neurotransmission, they still maintain significant levels of spontaneous neurotransmitter release. The physiological role of this residual spontaneous release after genetic deletion of syb2 has remained elusive. Recent studies have shown that alternative vesicular SNARE proteins such as VAMP4, VAMP7 (also called tetanus-insensitive or TI-VAMP) and Vps10p tail interactor 1 a (Vti1a) functionally diverge from syb2 and independently carry out spontaneous and some asynchronous neurotransmitter release. These studies demonstrated that these alternative vesicular SNAREs constitute molecular tags for independently functioning synaptic vesicle populations and provide a potential molecular basis for selective regulation of distinct forms of neurotransmitter release. In this application, we propose to examine the physiological impact of the forms of neurotransmitter release mediated by these alternative SNAREs. We will delineate how neurotransmitter release mediated by these alternative SNAREs directs neuronal signaling and synaptic efficacy via three Specific Aims. In the first aim, the synaptic scaling elicited by selective manipulation of spontaneous neurotransmitter release will be examined. The second aim will focus on the postsynaptic Ca2+ signals elicited by spontaneous neurotransmitter release. Finally, the third aim will investigate the regulation of synaptic plasticity by selective manipulation of spontaneous neurotransmitter release in an intact synaptic circuit. Collectively, these complementary experiments will elucidate how spontaneous neurotransmission modulates neuronal function in a physiological network. Information attained from these studies will provide new insight to the synaptic substrates that may be affected by a number of in neuropsychiatric and neurological disorders including major depressive disorder, autism and schizophrenia.