Kainate Receptors in Synaptic Transmission

突触传递中的红藻氨酸受体

• 批准号: 7017687
• 负责人: DIANA Leslie PETTIT
• 金额: $ 33.69万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017687
• 关键词: AMPA receptors; action potentials; biological signal transduction; brain electrical activity; confocal scanning microscopy; dendritic cells; electrophysiology; epilepsy; genetically modified animals; glutamate receptor; hippocampus; kainate; laboratory mouse; neural transmission; neurotoxicology; neurotransmitter transport; photolysis; protein localization; protein structure function; receptor expression; synapses

DESCRIPTION (provided by applicant): Kainate receptors (KARs) regulate neuronal excitability, and their global activation induces seizures and neuronal toxicity similar to that seen in epilepsy. Examination of KARs in synaptic function has largely focused on presynaptic KARs that appear to modulate neurotransmitter release. However, there is also clear evidence that KARs are located on the postsynaptic dendritic membranes of many neurons, and their role in synaptic physiology is unclear. KAR currents decay more slowly than AMPA currents, a property that may allow KARs to modulate the spread and integration of dendritic signals. Recent modeling of KAR function in response to afferent firing suggested that KAR activation could produce a tonic depolarization and increase neuronal excitability even at relatively low firing frequencies. This feature of KARs may confer a unique role in synaptic integration as well as in the timing and frequency of action potentials. While this is an intriguing hypothesis, it has not been directly tested. Our underlying hypothesis, based in part upon our preliminary data, is that postsynaptic KARs modulate firing frequency and integration of dendritic signaling in a cell-dependent manner. A direct test of this hypothesis will require examination of postsynaptic KARs in isolation from presynaptic KARs, with subcellular temporal and spatial resolution similar to that of synaptic activation. We will test the hypothesis that postsynaptic KARs are targeted to different dendritic regions of inhibitory and excitatory neurons in a cell-specific manner, and that postsynaptic dendritic KARs activation increases spike frequency in spontaneously firing inhibitory. Finally, we will test the hypothesis that postsynaptic dendritic KARs increase dendritic excitability and backpropagation of action potentials in hippocampal slice neurons. These experiments will be carried out using local photolysis, electrophysiology, and confocal imaging. These experiments will provide valuable new information about the role of postsynaptic, dendritic KARs in synaptic signaling and cell excitability.

描述（由申请人提供）：海藻酸盐受体（KARS）调节神经元兴奋性及其全球激活会诱导癫痫发作和神经元毒性，类似于癫痫中所见的毒性。对突触功能的KAR的检查主要集中在似乎调节神经递质释放的突触前KARS上。但是，也有明确的证据表明，KARS位于许多神经元的突触后树突状膜上，它们在突触生理中的作用尚不清楚。 KAR电流的衰减速度比AMPA电流较慢，AMPA电流可能使KARS可以调节树突信号的扩散和整合。 KAR功能响应传入发射的最新建模表明，即使在相对较低的射击频率下，KAR激活也可能产生滋补性去极化并增加神经元兴奋性。 KARS的这一特征可能赋予突触整合以及动作电位的时间和频率中的独特作用。尽管这是一个有趣的假设，但尚未直接测试。我们的基本假设部分基于我们的初步数据，是突触后KARS以细胞依赖性方式调节树突信号传导的频率和整合。对该假设的直接检验将需要从突触前KAR中分离出突触后KARS，其亚细胞时间和空间分辨率与突触激活相似。我们将检验以下假设：突触后KAR的靶向以细胞特异性方式针对抑制性和兴奋性神经元的不同树突状区域，并且突触后树突状KARS激活会增加自发性抑制性抑制性的峰值频率。最后，我们将检验以下假设：突触后树突状KAR会增加海马片神经元中的树突状兴奋性和作用电位的反向传播。这些实验将使用局部光解，电生理学和共聚焦成像进行。这些实验将提供有关突触后，树突状KAR在突触信号传导和细胞兴奋性中的作用的宝贵新信息。