GABA-A Receptor Alpha 1 Subunit Mutations and Epilepsy

描述（申请人提供）：GABA-A受体（GABAAR）α 1亚单位的突变最近与特发性全身性癫痫（IGE）综合征有关。神经元在发育中IGE综合征的症状通常出现时增加α 1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间破坏GABAAR表达和生理学，以便为这些癫痫综合征及其共病的新治疗和预防策略的开发提供机制基础。待检验的假设为：1）由于11亚基表达在整个发育过程中增加，GABRA 1癫痫突变将减少总GABAAR亚基蛋白，并在P19前产生相对于野生型神经元具有较小IPSC振幅的神经元，2）GABRA 1癫痫突变将增加来自突变小鼠的P19神经元中12-3亚基的相对表面表达，这是由于12-3亚基的相对表面表达增加。3与11亚基比率，以及3）由于11亚基表达在发育过程中增加，突变小鼠在P19时比在P12时表现出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在整个发育过程中对总GABAAR表达和IPSC幅度的影响，2）确定敲除和敲入突变在整个发育过程中对11-5亚基表达的影响，以及11-5亚基蛋白丰度与GABAAR掺入的关系，和3）确定敲除和敲入突变对GABAAR表达的影响。在癫痫和神经行为表型的发展中的突变。

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.