Analysis of Inhibitory Synaptic Proteins Associated with Brain Disorders

在美国，癫痫影响着大约230万成年人和45万儿童。每个人 去年，有15万公民被新诊断为癫痫。预计的成本 与癫痫相关的大约155亿美元的医疗费用和损失 收益(NINDS)。治疗癫痫相关疾病的进展是严重的 由于我们缺乏与分子机制相关的基本知识而受到阻碍 这是这种疾病的根本原因。我们最近在《科学》杂志上发表的研究使用了一本活体小说 化学遗传学方法鉴定抑制性突触后蛋白质组 这项研究得到了R21的支持，并发现了一个由多种蛋白质组成的大型复合体 在兴奋性神经元的GABA能突触的IPSD中富含。其中有几个是 由已知人类突变导致的基因编码的新蛋白质 癫痫。这笔赠款的具体目标建立在这些令人兴奋的发现和后续行动的基础上 关于我们最近的研究，重点是癫痫相关的可检验假说 IPSD蛋白编码基因突变通过损伤导致癫痫发作 抑制力。我们期待这些目标的结果将弥合我们的知识鸿沟 关于癫痫如何在体内出现异常的分子机制 抑制，为预防和可能的治疗带来了新的未来方向 这些障碍。

Epilepsy affects approximately 2.3 million adults and 450,000 children in the US. Each year, 150,000 citizens are newly diagnosed with epilepsy. The estimated cost associated with epilepsies is approximately 15.5 billion in medical expenses and lost earnings (NINDS). Progress in treating disorders associated with epilepsies is severely hampered by our lack of basic knowledge related to the molecular mechanisms underlying the disorder. Our recently published work in Science, used a novel in vivo chemico-genetic approach to identify the proteome of the inhibitory postsynapse (iPSD). This study was supported by an R21 and identified a large complex of proteins that are enriched at the iPSD of GABAergic synapses of excitatory neurons. Several of these are novel proteins encoded by genes for which human mutations are known to cause epilepsies. The specific aims of this grant build on these exciting findings and follow up on our recent study by focusing on the testable hypothesis that epilepsy-associated mutations in genes encoding proteins of the iPSD lead to seizures by impairing inhibition. We anticipate the results of these aims will bridge our knowledge gap regarding molecular mechanisms of how epilepsies emerge in vivo from abnormalities of inhibition, leading to new future directions for the prevention and possible treatments of these disorders.