AMPA RECEPTORS IN CALLOSAL SYNAPSES IN DEVELOPMENT

描述（由申请人提供）：AMPA类谷氨酸受体 介导大脑中的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受体家族的一个成员，GluR2亚基，占主导地位， 在成熟的新皮层兴奋性神经元之间的连接。没有 这种亚基改变AMPA受体的特性， 不渗透钙离子并显示使用依赖性促进作用。 在许多动物癫痫模型中已经注意到GluR2的下调 和人类癫痫中。该实验室最近证明，GluR2是 在锥体神经元突触受体中功能性表达， 在大鼠新皮层发育早期的水平。因此，在癫痫患者中， 皮质可能有一个重演的早期出生后表型， GluR2缺乏受体，假设在成人中是致癫痫的 个脑袋在这个建议中，全细胞电压钳技术和激光扫描 笼状谷氨酸光解将用于大鼠新皮层脑切片， 测试关于发育中GluR2改变的发现的一般性， 不同皮质区域和层的锥体神经元。此夕h 兴奋性突触回路的功能性后果， 将检查持续重复性、类似于催眠的活动。假设将 降低癫痫组织中GluR2亚单位的表达 导致突触受体的功能改变 增加钙离子进入和突触后促进，这两者都可能 在癫痫的发展过程中很重要。

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.