Transcriptional control of inhibitory synapse formation

近年来，在了解控制哺乳动物大脑突触发育的分子机制方面取得了重大进展。我们的实验室已经发现了活性调节bHLH转录因子Npas4在抑制性突触在兴奋性神经元上的发展以及对抑制性突触和兴奋性突触之间平衡的影响中的作用。为了了解Npas4在体内控制抑制性突触发育的机制，我们产生了携带cree介导的条件敲除突变的小鼠f\lpas4。使用这种条件敲除方法，我们将研究Npas4缺失对发育过程中不同时期抑制性突触形成和功能的影响。我们还将使用该小鼠模型来测试Npais4在发育中的视觉皮层中抑制性突触成熟和感觉经验介导的突触可塑性中的作用。此外，我们将结合染色质免疫沉淀测序和转录组测序，结合生物信息学分析，在全基因组范围内鉴定Npas4的DNA占用位点和Npas4调节的RNA转录本。这些研究将为Npas4控制的遗传程序提供新的见解，以介导其对哺乳动物大脑中抑制性突触发育的影响以及兴奋性和抑制性输入之间的平衡。这些研究将对我们理解认知功能障碍（如自闭症谱系障碍）是如何在微妙的兴奋/抑制平衡被破坏时出现的至关重要，并可能为这些疾病的治疗提供靶点。

Significant progress has been made recently towards understanding the molecular mechanisms that control synapse development in the mammalian brain. Our laboratory has uncovered a role for the activity-regulated bHLH transcription factor, Npas4, in the development of inhibitory synapses onto excitatory neurons and resulting effects on the balance between inhibitory and excitatory synapses. To understand the mechanism by which Npas4 controls inhibitory synapse development in vivo, we have generated mice that carry a cre-mediated conditional knockout mutation of f\lpas4 Using this conditional knockout approach, we will examine the effect of loss of Npas4 on inhibitory synapse formation and function at various times during development. We will also use this mouse model to test the role of Npais4 on inhibitory synapse maturation and sensory experience-mediated synaptic plasticity in the developing visual cortex. In addition, we will use a combination of chromatin immunoprecipitation-sequencing and transcriptome-sequencing in conjunction with bioinformatics analysis to identify on a genome-wide scale the DNA occupancy sites of Npas4 and the RNA transcripts that Npas4 regulates. These studies will provide new insights into the genetic program that Npas4 controls to mediate its effect on inhibitory synapse development and the balance between excitatory and inhibitory inputs in the mammalian brain. These studies will be crucial to our understanding of how disorders of cognitive function such as autism spectrum disorders may arise when the delicate excitatory/inhibitory balance is disrupted and may suggest targets for treatments of these diseases.