Asynchronous Release in Synaptic Transmission

 描述（由申请人提供）：突触前活性区释放神经递质是突触传递所需的基本过程。异常的突触传递是各种神经精神疾病的基础，例如精神分裂症和抑郁症。动作电位诱发的神经递质释放是由突触前钙的增加驱动的。称为突触结合蛋白的钙感应蛋白与钙结合并促进囊泡融合。诱发释放有两种模式：与突触前动作电位同相发生的快速同步释放和在动作电位激发后发生的缓慢异步释放。尽管同步释放已被广泛研究，但异步释放在突触传递中的作用尚不清楚。该研究的长期目标是阐明异步释放的分子基础和生理相关性。 Synaptotagmin-7 (Syt7) 先前已在体外被证明是异步释放的钙传感器。拟议的研究将利用 Syt7 敲除动物来检查 Syt7 是否介导体内异步释放，特别是来自海马胆囊收缩素 (CCK) 阳性中间神经元，其中异步释放尤为突出。将对 Syt7 敲除动物进行行为测试，以确定运动、焦虑、社交行为以及学习和记忆是否受损或异常。最后，将对海马 CCK 阳性中间神经元进行光遗传学操作，以确定这些神经元如何特异性调节动物的行为。这些实验将寻求将特定细胞类型（海马中的 CCK 中间神经元）中的特定分子过程（Syt7 介导的异步释放）与复杂的动物行为（学习和记忆）直接联系起来。

 DESCRIPTION (provided by applicant): The release of neurotransmitters from the presynaptic active zone is a fundamental process that is required for synaptic transmission. Abnormal synaptic transmission underlies various neuropsychiatric diseases such as schizophrenia and depression. Action potential evoked neurotransmitter release is driven by a rise in presynaptic calcium. Calcium-sensing proteins called synaptotagmins bind to calcium and facilitate vesicle fusion. There are two modes of evoked release: fast synchronous release that occurs in phase with the presynaptic action potential and slow asynchronous release which takes place after an action potential has fired. Although synchronous release has been studied extensively, the role of asynchronous release in synaptic transmission is not as well understood. The long-term goal of the proposed study is to elucidate the molecular basis and physiological relevance of asynchronous release. Synaptotagmin-7 (Syt7) has previously been shown in vitro to be the calcium sensor for asynchronous release. The proposed study will utilize Syt7 knockout animals to examine whether Syt7 mediates asynchronous release in vivo, specifically from hippocampal cholecystokinin (CCK)-positive interneurons where asynchronous release is particularly prominent. Behavioral tests will be performed on Syt7 knockout animals to determine whether locomotion, anxiety, social behaviors, and learning and memory are impaired or abnormal. Finally, optogenetic manipulations of hippocampal CCK-positive interneurons will be performed to determine how these neurons specifically modulate an animal's behavior. These experiments will seek to directly link a specific molecular process (Syt7-mediated asynchronous release) in a defined cell type (CCK-interneurons in the hippocampus) to complex animal behaviors (learning and memory).