Importance of TRPV channels in hippocampal synaptic depression

描述(申请人提供)：瞬时受体电位，香草酸(TRPV)，第1组通道亚家族包括四个成员：TRPV1，TRPV2，TRPV3和TRPV4。TRPV通道是一种温度敏感型非选择性阳离子通道，由多种内源性配体调控。目前正在测试TRPV1激动剂和拮抗剂在包括疼痛在内的多种疾病状态下的使用。TRPV通道的表达最初是在外周神经系统中报道的；然而，越来越多的证据表明，TRPV通道也在大脑中表达。关于TRPV的调制和激活如何影响大脑中的突触传递，人们知之甚少。我们的实验室最近发现，TRPV1通道对于海马CA1区GABA能中间神经元突触的抑制是必不可少的，CA1区是大脑中一个重要的学习和记忆区域。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。在海马神经元中发现TRPV1和TRPV3是钙离子通透性的阳离子通道，并触发突触变化，这对海马电路如何处理信息从而调节神经元网络具有重要的意义。我们推测，TRPV1和TRPV3通道对于兴奋性突触在海马区中间神经元上的突触抑制是必需的，这最终可能影响学习和记忆机制。因此，我们建议使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、情绪和认知过程。通过表征这种新形式的突触可塑性，我们的发现将提供有关海马功能的重要基本信息，并可能随着TRPV通道疗法的不断发展而被证明具有直接的临床意义。 公共卫生相关性：TRPV1和TRPV3是由各种内源性配体和热激活的通道蛋白。最近，TRPV通道被证明在海马区表达，海马区是大脑中对学习和记忆至关重要的区域。在这里，我们将测试TRPV1和TRPV3通道的激活是否对于大脑突触的变化是必要的，这些突触可能是学习或记忆的基础。

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.