TRPV1 Channels in hippocampal neurons

说明(申请人提供)：TRPV1通道是配基和热门离子通道，具有与NMDAR通道相当的钙渗透性。越来越多的证据支持这些通道在大脑中的表达和活性，最早是在周围神经系统的初级感觉传入神经元中发现和克隆的。我的实验室最近发表了第一个功能证据，证明海马锥体细胞上存在TRPV1通道。利用脑片的电生理方法，我们发现TRPV1通道对于一种形式的海马突触可塑性是必不可少的，这是第一个证据表明任何TRP通道都是突触可塑性所必需的。海马体是正常形成新的长期记忆所需的大脑区域。在海马神经元上发现一种新的高钙离子通透性阳离子通道及其触发突触变化的能力对海马神经元的信息处理具有重要的意义。此外，海马体几乎总是与颞叶癫痫有关。我们的证据表明，激活海马区TRPV1通道既可直接使兴奋性锥体神经元去极化，又可持续抑制对抑制性中间神经元的兴奋性驱动。这种效应的结合与癫痫的发展有关，因为它预计会促使海马体进入更易兴奋的状态。在这项提议中，我计划定义海马区TRPV1通道被激活的条件，使用锥体神经元兴奋性的变化和TRPV1激活所产生的突触功能的变化作为电生理分析。在外周神经系统中，TRPV1被认为是一种热激活离子通道。尽管大脑通常受到保护，不受温度变化的影响，但我们的初步数据表明，海马区TRPV1通道可能有助于热激活的癫痫活动。我们将开始探索TRPV1可能在发热性癫痫中发挥作用的想法，发热性癫痫是幼儿在发烧期间产生的癫痫，目前还没有有效的治疗方法。在拟议的实验中，我们将测试热和内源性配体对TRPV1通道的激活，以开始确定TRPV1通道改变海马区功能的条件。与公共健康相关：我们首次在海马体中发现了一种名为TRPV1的蛋白质，它被热和大脑中发现的天然化合物激活。海马体是正常学习和记忆所必需的，经常与人类癫痫发作障碍有关。TRPV1的热敏感性表明，这种蛋白可能导致幼儿发烧导致癫痫发作，这种疾病可能会发展为癫痫，目前还没有有效的治疗方法。在这里，我们将探索TRPV1促进海马区兴奋性的新假设，并可能代表癫痫发作的新治疗靶点。

DESCRIPTION (provided by applicant): TRPV1 channels are ligand- and heat-gated ion channels that have a calcium permeability comparable to NMDAR channels. First identified and cloned in primary sensory afferent neurons in the peripheral nervous system, mounting evidence supports the expression and activity of these channels in brain. My laboratory recently published the first functional evidence that TRPV1 channels are present on hippocampal pyramidal cells. Using electrophysiological methods in brain slices, we found that TRPV1 channels are essential for a form of hippocampal synaptic plasticity, the first evidence that any TRP channel is required for synaptic plasticity. The hippocampus is a brain region required for normal formation of new long-term memories. The discovery of a new, highly Ca2+permeable cation channel in hippocampal neurons and its ability to trigger synaptic changes has important implications for hippocampal information processing. Furthermore, the hippocampus is nearly always involved in temporal lobe epilepsy. Our evidence suggests that activation of hippocampal TRPV1 channels will both depolarize the excitatory pyramidal neurons directly, and persistently depress excitatory drive to inhibitory interneurons. This combination of effects is relevant to the development of epilepsy because it is expected to drive the hippocampus into a more excitable state. In this proposal I plan to define the conditions under which hippocampal TRPV1 channels are activated, using as electrophysiological assays both excitability changes in pyramidal neurons and alterations of synaptic function produced by TRPV1 activation. In the peripheral nervous system, TRPV1 has been characterized as a heat-activated ion channel. Although the brain is generally protected from large temperature changes, our preliminary data suggest that hippocampal TRPV1 channels may contribute to heat-activated seizure activity. We will begin to explore the idea that TRPV1 could play a role in febrile seizures, seizures generated in young children during fever for which there is currently no effective treatment. In the proposed experiments, we will test activation of TRPV1 channels by heat and endogenous ligands to begin to identify the conditions under which TRPV1 channels alter hippocampal function. PUBLIC HEALTH RELEVANCE: We have identified for the first time in the hippocampus, a region required for normal learning and memory and frequently implicated in human seizure disorders, a protein called TRPV1 that is activated by heat and natural compounds found in the brain. The heat-sensitivity of TRPV1 suggests that this protein could contribute to fever-induced seizures in young children, a disorder that can progress to epilepsy and that currently has no effective treatment. Here we will explore the novel hypothesis that TRPV1 contributes to hippocampal excitability, and could represent a novel therapeutic target for epileptic seizures.