Importance of TRPV channels in hippocampal synaptic depression

描述（由申请人提供）：瞬时受体电位，香草蛋白（TRPV）， 1组通道亚家族包括四个成员：TRPV1， TRPV2， TRPV3和TRPV4。TRPV通道是由多种内源性配体门控的热敏非选择性阳离子通道。TRPV1激动剂和拮抗剂目前正在测试用于多种疾病状态，包括疼痛。TRPV通道的表达最初是在周围神经系统中报道的；然而越来越多的证据表明TRPV通道也在大脑中表达。关于TRPV的调节和激活如何影响大脑中的突触传递，我们知之甚少。我们的实验室最近表明，TRPV1通道对于海马CA1区域gaba能中间神经元突触的抑制是必不可少的，CA1区域是学习和记忆的重要大脑区域。此外，我的初步数据表明TRPV3通道也是这种形式的突触抑制所必需的。TRPV1和TRPV3在海马神经元中作为Ca2+可渗透阳离子通道的发现及其对突触变化的触发对海马回路如何处理信息从而调节神经元网络具有重要意义。我们假设TRPV1和TRPV3通道都是海马中间神经元兴奋性突触突触抑制所必需的，这可能最终影响学习和记忆机制。因此，我们建议利用电生理和行为技术来表征TRPV1和TRPV3通道调节在突触传递中的意义，以及这些通道如何影响感觉、情绪和认知加工。通过表征这种突触可塑性的新形式，我们的发现将为海马功能提供重要的基础信息，并可能随着TRPV通道治疗方法的不断发展而被证明具有直接的临床相关性。

DESCRIPTION (provided by applicant): The transient receptor potential, vanilloid (TRPV), group 1 subfamily of channels includes four members: TRPV1, TRPV2, TRPV3 and TRPV4. TRPV channels are thermosensitive non- selective cation channels gated by a variety of endogenous ligands. TRPV1 agonists and antagonists are currently being tested for use in multiple disease states including pain. TRPV channel expression was originally reported in the peripheral nervous system; however growing evidence suggests that TRPV channels are also expressed in the brain. Little is known about how TRPV modulation and activation influences synaptic transmission in the brain. Our laboratory has recently shown that TRPV1 channels are essential for depression at synapses on GABAergic interneurons within the hippocampal CA1 region, a brain region important in learning and memory. Furthermore, my preliminary data suggests that TRPV3 channels are also required for this form of synaptic depression. The discovery of TRPV1 and TRPV3 as Ca2+ permeable cation channels in hippocampal neurons and their triggering of synaptic changes have important implications for how hippocampal circuits process information, thus modulating the neuronal network. We hypothesize that both TRPV1 and TRPV3 channels are necessary for synaptic depression of excitatory synapses on interneurons in the hippocampus, which may ultimately impact learning and memory mechanisms. Therefore, using electrophysiological and behavioral techniques we propose to characterize the significance of TRPV1 and TRPV3 channel regulation on synaptic transmission and how these channels influence sensory, emotive and cognitive processing. By characterizing this novel form of synaptic plasticity our findings will provide important basic information about hippocampal function and may prove to have direct clinical relevance as TRPV channel therapeutics continue to be developed. PUBLIC HEALTH RELEVANCE: TRPV1 and TRPV3 are channel proteins activated by various endogenous ligands and heat. Recently TRPV channels have been shown to be expressed in the hippocampus, a brain region important for learning and memory. Here we will test whether TRPV1 and TRPV3 channel activation is necessary for changes in brain synapses that may underlie aspects of learning or memory.