Role of Synaptotagmins in Synaptic Plasticity in the Hippocampus

描述(申请人提供)：学习和记忆需要使用依赖的突触功能和传输的改变，这一过程被称为突触可塑性。许多精神障碍，如精神分裂症、抑郁症和创伤后应激障碍，可能与突触可塑性异常有关。突触可塑性的一个主要模型是长时程增强(LTP)，它认为NMDA受体的激活增强了AMPA受体介导的传递，从而增加了兴奋性突触的强度。尽管经过了几十年的研究，但LTP背后的分子机制的许多方面仍然不清楚。这项拟议的研究将检验一种假说，即被称为突触素的钙结合蛋白调控AMPA受体向突触后膜的运输。众所周知，突触前突触聚集蛋白可以结合钙并触发神经递质释放。这项研究将在体内使用病毒介导的击倒和替换海马区CA1锥体细胞中的突触聚集蛋白。电生理记录将在急性海马片上进行，以确定这些操作对LTP和基础传输的影响。总之，这些实验将阐明突触后膜运输的机制，以及它们是如何参与突触可塑性的。了解这些机制有朝一日可能会为各种精神疾病带来新的治疗方法。

DESCRIPTION (provided by applicant): Learning and memory requires use-dependent changes in synaptic function and transmission, a process known as synaptic plasticity. Many mental disorders such as schizophrenia, depression, and post-traumatic stress disorder may be linked to abnormalities in synaptic plasticity. One leading model of synaptic plasticity is long-term potentiation (LTP), which proposes that NMDA receptor activation enhances AMPA receptor mediated transmission to increase the strength of excitatory synapses. Despite decades of research, many aspects of the molecular mechanism underlying LTP remain unclear. The proposed study will test the hypothesis that calcium binding proteins known as synaptotagmins regulate the trafficking of AMPA receptors to the postsynaptic membrane. Presynaptic synaptotagmins are known to bind calcium and trigger neurotransmitter release. This study will use in vivo viral-mediated knockdown and replacement of synaptotagmins in CA1 pyramidal cells of the hippocampus. Electrophysiological recordings will be performed in acute hippocampal slices to determine the effect of these manipulations on LTP and basal transmission. Overall, these experiments will elucidate mechanisms of postsynaptic membrane trafficking and how they are involved in synaptic plasticity. Understanding these mechanisms may one day lead to new treatments for a variety of psychiatric disorders.