AMPA RECEPTORS IN CALLOSAL SYNAPSES IN DEVELOPMENT

描述（由申请人提供）：AMPA 类谷氨酸受体 介导大脑中大部分兴奋性神经传递。这些 受体特别涉及癫痫发作活动的传播。 AMPA 受体家族的一员 GluR2 亚基占主导地位 成熟新皮质中兴奋性神经元之间的连接。缺席 该亚基改变 AMPA 受体的特性，使其成为 钙离子不可渗透，并显示出使用依赖性的促进作用。 在许多动物癫痫模型中都发现 GluR2 下调 以及人类癫痫症。该实验室最近证明 GluR2 在锥体神经元突触受体中功能性表达非常低 大鼠新皮质发育早期的水平。由此可见，在癫痫病中 大脑皮层可能再现了出生后早期表型 缺乏 GluR2 的受体，被认为在成人中具有致癫痫作用 大脑。在该提案中，全细胞电压钳技术和激光扫描 笼式谷氨酸光解作用将与大鼠新皮质脑切片一起使用 测试关于发育中 GluR2 改变的发现的普遍性 不同皮质区域和层的锥体神经元。此外， 关于兴奋性突触回路能力的功能后果 将检查持续重复的、类似癫痫发作的活动。该假设将 经测试，癫痫组织中 GluR2 亚基的表达降低 导致突触受体的功能改变，从而允许 增加钙进入和突触后促进，两者都可能 在癫痫的发生发展中起重要作用。

DESCRIPTION (provided by applicant): The AMPA class of glutamate receptors mediate the majority of excitatory neurotransmission in the brain. These receptors are specifically implicated in the propagation of seizure activity. One member of the AMPA receptor family, the GluR2 subunit, dominates connections between excitatory neurons in the mature neocortex. The absence of this subunit alters the properties of AMPA receptors such that they become impermeable to calcium ions and show use-dependent facilitation. Down-regulations in GluR2 have been noted in a number of animal epilepsy models and in human epilepsy. This laboratory has recently demonstrated that GluR2 is functionally expressed in pyramidal neuron synaptic receptors at very low levels early in rat neocortical development. Thus it appears that in epileptic cortex there may be a recapitulation of the early postnatal phenotype of GluR2-lacking receptors, which are hypothesized to be epileptogenic in adult brain. In this proposal, whole cell voltage-clamp techniques and laser-scanning caged-glutamate photolysis will be used with rat neocortical brain slices to test the generality of the finding regarding developmental GluR2 alterations in pyramidal neurons of different cortical regions and lamina. Further, the functional consequence regarding the ability of excitatory synaptic circuits to sustain repetitive, seizure-like activity will be examined. The hypothesis will be tested that decreased expression of GluR2 subunits in epileptic tissue results in a functional alteration in the synaptic receptors that would allow for increased calcium entry and post-synaptic facilitation, both of which may be important in the development of epilepsy.