Transcriptional control of inhibitory synapse formation

最近在了解哺乳动物大脑中控制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的bHLH转录因子Npas4在抑制性突触向兴奋性神经元的发展以及由此对抑制性突触和兴奋性突触之间的平衡产生影响中的一个作用。为了了解Npas4在体内控制抑制性突触发育的机制，我们利用这种条件基因敲除方法产生了cre介导的条件基因敲除突变的小鼠，我们将检测Npas4的缺失对发育过程中不同阶段抑制性突触形成和功能的影响。我们还将使用此鼠标 测试Npais4对抑制性突触成熟和感觉经验调节作用的模型 发育中的视皮层中突触的可塑性。此外，我们还将结合使用 铬翅免疫沉淀测序和转录组测序联合应用 生物信息学分析，在全基因组范围内确定Npas4的DNA占位位置和Npas4调控的RNA转录本。这些研究将提供对遗传基因的新见解 Npas4控制的程序，以调节其对抑制性突触发育的影响 哺乳动物大脑中兴奋性和抑制性输入之间的平衡。这些研究将是 对于我们理解自闭症等认知功能障碍是如何 当微妙的兴奋/抑制平衡被破坏时，可能会出现紊乱，并可能建议这些疾病的治疗靶点。

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 transcripfion 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 funcfion at various fimes during development. We will also use this mouse model to test the role of Npais4 on inhibitory synapse maturafion and sensory experience-mediated synaptic plasficity in the developing visual cortex. In addifion, we will use a combination of chromafin immunoprecipitafion-sequencing and transcriptome-sequencing in conjunction with bioinformafic 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 funcfion such as aufism spectrum disorders may arise when the delicate excitatory/inhibitory balance is disrupted and may suggest targets for treatments of these diseases.