GABA-A Receptor Alpha 1 Subunit Mutations and Epilepsy

描述（由申请人提供）：GABA-A受体（GABAAR）α1亚基的突变最近已与特发性全身性癫痫（IGE）综合征相关。在 IGE 综合征症状通常出现的发育时期，神经元会增加 α1 亚基的表达。我们的长期目标是了解这些突变如何在发育的特定时期破坏 GABAAR 表达和生理学，以便为这些癫痫综合征及其共病状况的新治疗和预防策略的开发提供机制基础。要测试的假设是：1) 因为 11 亚基表达在整个发育过程中增加，GABRA1 癫痫突变将减少总 GABAAR 亚基蛋白，并在 P19 时产生相对于野生型神经元具有更小的 IPSC 幅度的神经元，2) 由于 12-3 与 11 亚基比率增加，GABRA1 癫痫突变将增加突变小鼠 P19 神经元中 12-3 亚基的相对表面表达，3) 因为11 亚基表达在发育过程中增加，突变小鼠在 P19 时将表现出比 P12 更严重的癫痫和神经行为表型。具体目标是：1)确定敲除和敲入突变对整个发育过程中GABAAR总表达和IPSC振幅的影响，2)确定敲除和敲入突变对整个发育过程中11-5亚基表达的影响以及11-5亚基蛋白质丰度与GABAAR掺入的关系，3)确定敲除和敲入突变对癫痫和神经行为发展的影响表型。

DESCRIPTION (provided by applicant): Mutations of the GABA--A receptor (GABAAR) alpha 1 subunit have recently been associated with idiopathic generalized epilepsy (IGE) syndromes. Neurons increase the expression of the alpha 1 subunit at the times in development when the symptoms of the IGE syndromes typically arise. Our long term goal is to understand how these mutations disrupt GABAAR expression and physiology at specific times in development in order to provide a mechanistic basis for the development of new treatment and prevention strategies for these epilepsy syndromes and their co-morbid conditions. The hypotheses to be tested are: 1) because 11 subunit expression increases throughout development, GABRA1 epilepsy mutations will reduce total GABAAR subunit protein and produce neurons with smaller IPSC amplitudes relative to wild type neurons by P19, 2) the GABRA1 epilepsy mutations will increase the relative surface expression of 12-3 subunits in P19 neurons from mutant mice due to an increased 12-3 to 11 subunit ratio, and 3) because 11 subunit expression increases during development, mutant mice will demonstrate more severe epileptic and neurobehavioral phenotypes at P19 than at P12. The specific aims are: 1) determine the effects of the knock-out and knock-in mutations on total GABAAR expression and IPSC amplitudes throughout development, 2) determine the effects of knock-out and knock-in mutations on expression of 11-5 subunits throughout development and the relationship of 11-5 subunit protein abundance to incorporation in GABAAR and 3) determine the effects of the knock-out and knock-in mutations on the development of the epilepsy and neurobehavioral phenotypes.