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

剖析 GABAA 受体 B3 亚基的离体和体内功能

基本信息

批准号：
10244871
负责人：
Quynh Anh Nguyen
金额：
$ 3.32万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10244871
关键词：
Acute Address Affect Anatomy Antiepileptic Agents Behavioral Binding Biological Brain Brain region CRISPR/Cas technology Calcium Cells Computer Analysis Computer Models Data Development Distal Electrophysiology (science)Epilepsy Exhibits Foundations Functional disorder Future Generations Genes Genetic Hippocampus (Brain)Human Image Interneurons Knock-out Lead Methods Modeling Mus Mutation Neurologic Dysfunctions Neurons Neurotransmitters Parvalbumins Patients Pattern Play Population Predisposition Property Pyramidal Cells Recurrence Reporter Role Seizures Signal Transduction Slice Somatostatin Synapses Synaptic Transmission Testing Therapeutic Intervention United States Work cell type experimental study gamma-Aminobutyric Acid improved in vivo insight nervous system disorder neuronal circuitry patch clamp receptor side effect tool transmission process treadmill

项目摘要

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.

无法调节神经元的放电特性通常会导致异常和过度的活动导致癫痫发作GABAA受体对于抑制信号的传递至关重要，该抑制信号作为制动器，过度活动来控制和协调神经元功能。GABAA受体β3亚基缺陷与人类癫痫有关，缺乏β3的小鼠也会出现癫痫发作。但是，底层 β3缺失导致癫痫易感性的机制仍不清楚。我的初步数据显示海马CA1区锥体细胞β3基因的敲除会影响抑制性神经元从特定亚群的传递，细胞，但这些细胞的确切身份仍有待确定。此外，整个网络的变化海马细胞的活动导致这些特定连接的缺陷，以及这些变化如何导致癫痫病仍有待解决。我的目标是利用遗传学、电生理学、成像和计算模型方法来检验海马CA1区β3亚基丢失导致海马CA1区β3亚基丢失的假设。在特定的电路和网络水平的中断潜在的癫痫发作的敏感性。这些研究将为确定治疗干预的潜在途径，同时阐明癫痫发作和癫痫的基本机制。