Kainate Receptors in Synaptic Transmission

描述（由申请人提供）：红藻氨酸受体（KAR）调节神经元兴奋性，其整体激活诱导癫痫发作和神经元毒性，类似于癫痫中所见。对KAR在突触功能中的研究主要集中在突触前KAR上，它们似乎调节神经递质的释放。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，它们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KAR功能的传入放电响应模型表明，KAR激活可以产生紧张性去极化，增加神经元的兴奋性，即使在相对较低的放电频率。KARs的这一特征可能在突触整合以及动作电位的时间和频率中发挥独特的作用。虽然这是一个有趣的假设，但它尚未得到直接验证。我们的基本假设，部分基于我们的初步数据，是突触后KARs调制放电频率和树突状信号的整合在细胞依赖性的方式。对这一假设的直接检验需要将突触后KAR与突触前KAR分离开来进行检查，亚细胞时间和空间分辨率与突触激活相似。我们将测试的假设，即突触后KARs有针对性的抑制性和兴奋性神经元的不同树突状区域的细胞特异性的方式，和突触后树突状KARs激活增加尖峰频率自发发射抑制。最后，我们将测试的假设，突触后树突KAR增加树突的兴奋性和反向传播的海马切片神经元的动作电位。这些实验将使用局部光解、电生理学和共聚焦成像进行。这些实验将提供有价值的新信息的作用，突触后，树突状KARs在突触信号和细胞兴奋性。

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.