Kainate Receptors in Synaptic Transmission

突触传递中的红藻氨酸受体

• 批准号: 6925015
• 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/6925015
• 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）：红藻氨酸受体（KAR）调节神经元兴奋性，其整体激活会诱发类似于癫痫的癫痫发作和神经元毒性。对突触功能中 KAR 的检查主要集中在似乎调节神经递质释放的突触前 KAR。然而，也有明确的证据表明KAR位于许多神经元的突触后树突膜上，其在突触生理学中的作用尚不清楚。 KAR 电流比 AMPA 电流衰减得更慢，这一特性可能允许 KAR 调节树突信号的传播和整合。最近响应传入放电的 KAR 功能模型表明，即使在相对较低的放电频率下，KAR 激活也可以产生强直去极化并增加神经元兴奋性。 KAR 的这一特征可能在突触整合以及动作电位的时间和频率方面发挥独特的作用。虽然这是一个有趣的假设，但尚未经过直接检验。我们的基本假设（部分基于我们的初步数据）是，突触后 KAR 以细胞依赖性方式调节树突信号传导的放电频率和整合。对这一假设的直接检验需要将突触后 KAR 与突触前 KAR 分开进行检查，亚细胞时间和空间分辨率与突触激活相似。我们将测试以下假设：突触后 KAR 以细胞特异性方式靶向抑制性和兴奋性神经元的不同树突区域，并且突触后树突 KAR 激活会增加自发放电抑制的尖峰频率。最后，我们将检验突触后树突 KAR 增加海马切片神经元树突兴奋性和动作电位反向传播的假设。这些实验将利用局部光解、电生理学和共焦成像进行。这些实验将提供关于突触后树突 KAR 在突触信号传导和细胞兴奋性中的作用的有价值的新信息。