Role of SNARE Interactions in Central Synapse Function

描述(申请人提供)：在中枢突触中，Synaptobrevin2(Syb2，也称为VAMP2)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，它与质膜SNAP-25和Synaxin1相互作用，执行胞吐作用。然而，虽然缺乏syb2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的自发神经递质释放水平。在syb2基因缺失后这种残留的自发释放的生理作用仍然难以捉摸。最近的研究表明，VAMP4、VAMP7(也称为破伤风不敏感或TI-VAMP)和Vps10p尾部相互作用蛋白1a(Vti1a)等替代水泡圈套蛋白在功能上与syb2背道而驰，独立地进行自发的和一些异步的神经递质释放。这些研究表明，这些可供选择的水泡圈套构成了具有独立功能的突触小泡群体的分子标记，并为选择性调节不同形式的神经递质释放提供了潜在的分子基础。在这一应用中，我们建议检查由这些替代陷阱介导的神经递质释放形式的生理影响。我们将描述由这些替代圈套介导的神经递质释放如何通过三个特定的目的引导神经元信号和突触效能。在第一个目的中，将研究选择性地操纵自发神经递质释放所引起的突触伸缩。第二个目标将集中在自发神经递质释放引起的突触后钙信号。最后，第三个目标将通过选择性地操纵完整突触回路中的自发神经递质释放来研究突触可塑性的调节。总的来说，这些互补性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为突触底物提供新的见解，这些突触底物可能会受到许多神经精神和神经疾病的影响，包括严重抑郁障碍、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.