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中的作用，从而对抑制性和兴奋性突触之间的平衡产生影响。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，我们将检测在发育过程中不同时间Npas4对抑制性突触形成和功能的影响。我们还将使用这个小鼠模型来测试Npais4在发育中的视皮层中抑制突触成熟和感觉经验介导的突触可塑性方面的作用。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，在全基因组范围内识别Npas4的DNA占据位点和Npas4调控的RNA转录本。这些研究将为Npas4控制的遗传程序提供新的见解，以调节其对哺乳动物大脑中抑制性突触发育和兴奋性和抑制性输入之间的平衡的影响。这些研究对于我们理解当微妙的兴奋/抑制平衡被破坏时，认知功能障碍(如自闭症谱系障碍)是如何发生的至关重要，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.