GABA-A Receptor Alpha 1 Subunit Mutations and Epilepsy

GABA-A 受体 Alpha 1 亚基突变与癫痫

• 批准号: 7889990
• 负责人: MARTIN J GALLAGHER
• 金额: $ 33.91万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7889990
• 关键词: Absence Epilepsy; Acoustics; Affect; Brain; Cells; Chemicals; Comorbidity; Development; Disease; Disinhibition; Epilepsy; Etiology; GABA-A Receptor; Generalized Epilepsy; Genes; Genetic; Goals; Juvenile Myoclonic Epilepsy; Knock-in Mouse; Knock-out; Learning; Left; Ligand Binding; Link; Medical; Messenger RNA; Motor Activity; Mutant Strains Mice; Mutate; Mutation; Neurons; Nonsense-Mediated Decay; Pharmaceutical Preparations; Phenotype; Physiology; Play; Polygenic Traits; Prevention strategy; Protein Subunits; Radiolabeled; Relative (related person); Research; Residual state; Resistance; Role; Seizures; Sensory; Slice; Surface; Symptoms; Synapses; Syndrome; Testing; Time; Tissues; Work; base; brain tissue; functional loss; mouse model; nervous system disorder; neurobehavioral; neuropsychiatry; novel; protein expression; public health relevance; radiotracer; receptor; receptor expression; research study

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. PUBLIC HEALTH RELEVANCE: Epilepsy is a common neurological disorder that is resistant to medication in one third of the cases. Genetic factors play a role in many forms of epilepsy. The experiments in this proposal will determine the effects of mutations an epilepsy gene and will thus provide crucial information for the development of novel epilepsy therapies.

描述(由申请人提供)：GABA-A受体(GABAAR)α1亚单位的突变最近被认为与特发性全身性癫痫(IGE)综合征有关。神经元在发育过程中增加α1亚单位的表达，此时通常会出现IgE综合征的症状。我们的长期目标是了解这些突变是如何在发育的特定时间扰乱GABAAR的表达和生理的，以便为开发这些癫痫综合征及其共病条件的新的治疗和预防策略提供机制基础。要检验的假设是：1)由于11个亚基在整个发育过程中都在表达增加，GABRA1癫痫突变将减少总的GABAAR亚基蛋白，并产生比野生型神经元更小的IPSC幅度的神经元P19，2)GABRA1癫痫突变将增加12-3亚基的相对表面表达，因为12-3至11亚基的比例增加，3)由于11亚基在发育过程中增加，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。其具体目的是：1)确定敲除和敲入突变对整个发育过程中GABAAR总表达和IPSC幅值的影响，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亚基蛋白丰度与GABAAR掺入的关系，以及3)确定敲除和敲入突变对癫痫和神经行为表型发展的影响。 与公共卫生相关：癫痫是一种常见的神经疾病，在三分之一的病例中对药物具有抵抗力。遗传因素在多种形式的癫痫中起着作用。这项建议中的实验将确定癫痫基因突变的影响，从而为开发新的癫痫治疗方法提供关键信息。