Dissecting the function of the B3 subunit of the GABAA receptor ex vivo and in vivo

不能调节神经元的放电特性往往会导致异常和过度的活动。 导致癫痫发作。GABAA受体对抑制信号的传递至关重要，抑制信号起到刹车的作用 控制和协调神经功能的过度活动。GABAA受体β3亚单位缺陷 在人类中被认为与癫痫有关，缺乏β3的小鼠会出现癫痫发作。然而，潜在的 β3丢失如何导致癫痫易感性的机制仍不清楚。我的初步数据显示 海马区CA1区锥体细胞中β3基因敲除影响特定抑制性亚群的传递 细胞，但这些细胞的确切身份仍有待确定。此外，整个网络的变化 由于这些特定连接的缺陷而导致的海马细胞的活动，以及这些变化如何导致 对癫痫的治疗仍有待解决。我的目标是利用遗传学、电生理学、成像和计算 模型方法检验假设海马区β3亚单位丢失会导致 在特定的电路和网络层面的干扰是癫痫发作的潜在易感性。这些研究将为 确定潜在的治疗干预途径的基础，同时阐明 癫痫发生和癫痫的基本机制。

The inability to regulate the firing properties of neurons can lead to aberrant and excessive activity, oftentimes causing seizures. GABAA receptors are crucial for transmission of inhibitory signals which act as a brake on excessive activity to control and coordinate neuronal function. Deficits in the β3 subunit of the GABAA receptor have been implicated in epilepsy in humans, and mice lacking β3 suffer from seizures. However, the underlying mechanism for how loss of β3 leads to susceptibility to seizures is still unknown. My preliminary data suggests that knockout of β3 in hippocampal CA1 pyramidal cells affects transmission from a specific subset of inhibitory cells, but the precise identity of those cells remains to be determined. In addition, changes to the overall network activity of hippocampal cells resulting from deficits to these specific connections, and how these changes lead to epilepsy remains to be resolved. I aim to use genetic, electrophysiological, imaging, and computational modeling methods to test the hypothesis that loss of the β3 subunit in the CA1 region of the hippocampus results in specific circuit and network level disruptions underlying susceptibility to seizures. These studies will lay a foundation for the identification of potential avenues for therapeutic intervention while simultaneously elucidating basic mechanisms underlying seizure generation and epilepsy.