TRPV1 Channels in hippocampal neurons

海马神经元中的 TRPV1 通道

• 批准号: 7730839
• 负责人: Julie A. Kauer
• 金额: $ 44.03万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730839
• 关键词: Affect; Afferent Neurons; Age; Biological Assay; Brain; Brain region; Calcium; Cations; Child; Data; Development; Disease; Epilepsy; Excitatory Synapse; Febrile Convulsions; Fever; Gated Ion Channel; Heating; Hippocampus (Brain); Human; Interneurons; Ion Channel; Laboratories; Lead; Learning; Ligands; Long-Term Depression; Memory; Methods; Mus; Neuromodulator; Neurons; Pathway interactions; Peripheral Nervous System; Permeability; Physiological; Play; Predisposition; Proteins; Publishing; Pyramidal Cells; Ramp; Reverse Transcriptase Polymerase Chain Reaction; Role; Second Messenger Systems; Seizures; Sensory; Signal Pathway; Slice; Synapses; Synaptic plasticity; TRP channel; TRPV channel; TRPV1 gene; Temperature; Temporal Lobe Epilepsy; Testing; Time; Wild Type Mouse; Work; depressed; effective therapy; hippocampal pyramidal neuron; information processing; long term memory; neuronal excitability; neurotransmitter release; new therapeutic target; novel; presynaptic; public health relevance; research study; response; second messenger; synaptic depression; synaptic function

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.

描述（由申请方提供）：TRPV1通道是配体门控和热门控离子通道，其钙渗透性与NMDAR通道相当。这些通道首先在外周神经系统的初级感觉传入神经元中被发现和克隆，越来越多的证据支持这些通道在大脑中的表达和活动。我的实验室最近发表了第一个功能性证据，证明TRPV1通道存在于海马锥体细胞上。在脑切片中使用电生理学方法，我们发现TRPV1通道对于海马突触可塑性的一种形式是必不可少的，这是突触可塑性需要任何TRP通道的第一个证据。海马体是一个大脑区域，是正常形成新的长期记忆所必需的。在海马神经元中发现一种新的高钙渗透性阳离子通道及其触发突触变化的能力对海马信息处理具有重要意义。此外，海马几乎总是参与颞叶癫痫。我们的证据表明，海马TRPV1通道的激活将直接降低兴奋性锥体神经元的兴奋性驱动，并持续抑制抑制中间神经元的兴奋性驱动。这种效应的组合与癫痫的发展有关，因为它有望将海马体驱动到更易兴奋的状态。在这个建议中，我计划定义海马TRPV1通道被激活的条件下，使用作为电生理检测锥体神经元的兴奋性变化和由TRPV1激活产生的突触功能的改变。在外周神经系统中，TRPV1被表征为热激活离子通道。虽然大脑通常受到保护，免受大的温度变化，我们的初步数据表明，海马TRPV1通道可能有助于热激活癫痫发作活动。我们将开始探索TRPV 1可能在热性惊厥中发挥作用的想法，热性惊厥是幼儿在发烧期间产生的惊厥，目前还没有有效的治疗方法。在所提出的实验中，我们将测试热和内源性配体对TRPV 1通道的激活，以开始鉴定TRPV 1通道改变海马功能的条件。 公共卫生相关性：我们首次在海马体中发现了一种名为TRPV1的蛋白质，该蛋白质是正常学习和记忆所需的区域，并且经常与人类癫痫发作有关，该蛋白质被大脑中发现的热和天然化合物激活。TRPV1的热敏感性表明，这种蛋白质可能导致幼儿发热诱导的癫痫发作，这种疾病可能进展为癫痫，目前没有有效的治疗方法。在这里，我们将探讨TRPV1有助于海马兴奋性的新假设，并可能代表癫痫发作的新治疗靶点。