The Role of GABAergic Synaptic Plasticity in Neural Circuit Functions

描述(申请人提供)：GABA能突触是大脑中主要的抑制性连接，可能在包括学习和记忆在内的所有大脑功能中发挥重要作用。GABA能突触的缺陷通常与毁灭性的疾病有关，如自闭症、精神分裂症和癫痫。尽管它们很重要，但关于GABA能突触的调节和功能的许多基本问题仍然没有答案。我们的长期目标是探索在行为体验中神经元活动与GABA能突触修改耦合的细胞和分子机制，并了解这种形式的GABA能突触可塑性的破坏如何导致认知缺陷。为了实现这一目标，我们最近发现了活性调节的bHLH-PAS转录因子Npas4，它是GABA能突触的关键调节因子。Npas4由兴奋性突触活动迅速诱导，其水平决定了兴奋性神经元上形成的GABA能突触的数量。这些发现表明，Npas4是神经元兴奋和GABA能突触之间的分子联系。通过研究Npas4的S在调节GABA能突触的活性依赖性调制和调节神经回路的行为输出中的作用，本文概述的研究计划将为许多神经疾病的病因提供新的见解。

DESCRIPTION (provided by applicant): GABAergic synapses are the major inhibitory connections in the brain and likely play an important role in all brain functions, including learning and memory. A deficit in GABAergic synapses is often implicated in devastating disorders such as autism, schizophrenia, and epilepsy. Despite their importance, many fundamental questions regarding the regulation and function of GABAergic synapses remain unanswered. Our long-term goal is to explore the cellular and molecular mechanisms by which neuronal activity is coupled to modification of GABAergic synapses during behavioral experience and to understand how disruption of this form of GABAergic synaptic plasticity leads to cognitive deficits. Towards this goal, we have recently identified the activity-regulated bHLH-PAS transcription factor Npas4 as a key regulator of GABAergic synapses. Npas4 is rapidly induced by excitatory synaptic activity and its level determines the number of GABAergic synapses formed on excitatory neurons. These findings suggest that Npas4 is the molecular link between neuronal excitation and GABAergic synapses. By investigating Npas4's role in regulating activity-dependent modulation of GABAergic synapses and regulating behavioral output of neural circuits, the research plan outlined here will yield new insights into the etiology of many neurological disorders.