AMPA RECEPTORS IN CALLOSAL SYNAPSES IN DEVELOPMENT

描述(申请人提供)：AMPA类谷氨酸受体 调节大脑中大部分的兴奋性神经传递。这些 受体与癫痫活动的传播有明确的关系。 AMPA受体家族中的一个成员，GluR2亚单位，占主导地位 成熟新皮质内兴奋性神经元之间的联系。不存在 这个亚基改变AMPA受体的特性，使它们成为 对钙离子不渗透，并表现出使用依赖的便利性。 在许多动物癫痫模型中已经注意到GluR2的下调 在人类癫痫中。这个实验室最近证明了GluR2是 在锥体神经元突触受体中的功能表达很低 在大鼠新皮质发育早期的水平。因此，似乎在癫痫患者中 皮质中可能有早期出生后表型的重现。 GluR2缺乏受体，被认为是成人致痫因素 大脑。在本方案中，全单元电压钳制技术和激光扫描 笼式谷氨酸光解将用于大鼠新皮质脑片 测试关于发育中GluR2改变的发现的一般性 不同皮质区域和板层的锥体神经元。此外， 关于兴奋性突触回路能力的功能结果 将检查持续重复的、癫痫样活动。这一假说将 经检测癫痫组织中GluR2亚单位表达减少 导致突触受体的功能改变，这将使 增加钙离子进入和突触后促进，这两者都可能 在癫痫的发生发展中起着重要作用。

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.