Role of TRPV1 channels in synaptic transmission and plasticity in the hippocampus

描述（由申请人提供）： 兴奋性和抑制性传递的突触功效的变化可以扰乱大脑内兴奋和抑制的微妙平衡，从而深刻地调节认知过程。这项研究计划的总体目标是了解TRPV1（一种非选择性阳离子通道）可能参与海马和齿状回兴奋性和抑制性突触的突触功效调制的机制，这两个关键的大脑区域参与学习和记忆形成，TRPV1高度表达。TRPV1通常被认为在突触前表达，并且可能被包括内源性大麻素（eCB）在内的不同脂质配体逆行激活。本文提出的实验旨在测试TRPV1可能在突触后起作用以减少谷氨酸和GABA受体的数量或反应性的可能性。此外，我将测试的可能性，eCB，通常通过激活突触前大麻素受体以逆行方式发出信号，也可以自分泌方式通过TRPV1调节突触后受体功能。首先，我将分析TRPV1激活的细胞和分子机制，以及TRPV1介导的CNS突触生理效应的下游机制。其次，我将扩大我们的分析，以了解几个G蛋白偶联受体在调节TRPV1介导的突触效能变化的贡献。这些信息对于更好地理解大脑TRPV1在调节突触和神经回路功能中的作用至关重要。 公共卫生相关性： TRPV1通道最近已成为开发控制外周神经系统疼痛的新药的有吸引力的分子靶点。不希望的副作用可能来自未知的和以前未探索的TRPV1在中枢神经系统中的功能。揭示TRPV1在中枢神经系统中的作用不仅与新型镇痛策略的开发有关，而且还可能为正常和病理生理条件下脑功能的细胞基础提供新的见解。

DESCRIPTION (provided by applicant): Brief Summary Changes in the synaptic efficacy of excitatory and inhibitory transmission can perturb the delicate balance of excitation and inhibition within the brain and thus profoundly modulate cognitive processes. The overall goal of this research proposal is to understand the mechanisms by which TRPV1, a non-selective cation channel, may be involved in the modulation of synaptic efficacy at both excitatory and inhibitory synapses in the hippocampus and dentate gyrus, two key brain areas involved in learning and memory formation and where TRPV1 is highly expressed. TRPV1 is generally thought to be expressed presynaptically, and might retrogradely be activated by different lipid ligands including endocannabinoids (eCBs). The experiments proposed here are designed to test the possibility that TRPV1 may act postsynaptically to reduce the number or responsiveness of glutamate and GABA receptors. In addition, I will test the possibility that eCBs, which typically signal in a retrograde manner by activating presynaptic cannabinoid receptors, could also act in an autocrine manner to regulate postsynaptic receptor function via TRPV1. First, I will analyze the cellular and molecular mechanism underlying TRPV1 activation as well as the mechanism downstream by which TRPV1-mediated physiological effect at CNS synapses. Second, I will expand our analyses to understand the contribution of several G-protein coupled receptors in regulating TRPV1- mediated changes of synaptic efficacy. This information is essential to gain a better understanding on the role of brain TRPV1 in regulating synaptic and neural circuit function. PUBLIC HEALTH RELEVANCE: TRPV1 channels have recently become an attractive molecular target for the development of new drugs to control pain in the peripheral nervous system. Undesirable side-effects may arise from unknown and previously unexplored TRPV1 functions in the central nervous system. Unmasking the role of TRPV1 in the central nervous system is not only relevant to the development of novel analgesic strategies but it may also provide new insights into the cellular basis underlying brain function under normal and pathophysiological conditions.