Transcriptional control of inhibitory synapse formation

抑制性突触形成的转录控制

• 批准号: 8322135
• 负责人: MICHAEL ELDON GREENBERG
• 金额: $ 30.33万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8322135
• 关键词: Acute; Address; Adult; Autistic Disorder; BHLH Protein; Bioinformatics; Brain; Calcium; Calcium Channel; Cell Lineage; Cells; Chromatin; Chronic; Cognition; Cognition Disorders; Complement; DNA; Data Analyses; Defect; Development; Developmental Process; Disease; Epilepsy; Equilibrium; Excitatory Synapse; Family; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Programming; Glutamates; Helix-Turn-Helix Motifs; Human; Inhibitory Synapse; Interneurons; Knock-out; Laboratories; Lead; Light; Link; Maintenance; Mediating; Mediator of activation protein; Molecular; Motor; Mouse Strains; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Nature; Nervous system structure; Neuraxis; Neurons; Physiological Processes; Process; RNA; RNA Interference; Regulation; Regulator Genes; Role; Schizophrenia; Sensory; Site; Stimulus; Synapses; Synaptic Transmission; Techniques; Testing; Transcript; Transcriptional Regulation; Visual Cortex; Visual system structure; area striata; autism spectrum disorder; base; cognitive function; excitatory neuron; experience; genome-wide; in vivo; insight; member; mouse model; nerve stem cell; nervous system disorder; neural circuit; novel; overexpression; prevent; programs; research study; response; synaptogenesis; voltage

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.

近年来，对哺乳动物大脑中控制突触发育的分子机制的研究取得了重大进展。我们的实验室已经发现了活性调节的bHLH转录因子Npas 4在兴奋性神经元上的抑制性突触的发育中的作用，以及对抑制性和兴奋性突触之间的平衡的影响。为了理解Npas 4在体内控制抑制性突触发育的机制，我们已经产生了携带cre介导的条件性敲除突变的fpas 4的小鼠。使用这种条件性敲除方法，我们将检查Npas 4缺失对发育期间不同时期抑制性突触形成和功能的影响。我们也会用这个鼠标 模型来测试Npais 4对抑制性突触成熟和感觉经验介导的 发育中的视觉皮层中的突触可塑性。此外，我们还将使用 染色质免疫沉淀测序和转录组测序结合 生物信息学分析以在全基因组范围内鉴定Npas 4的DNA占据位点和Npas 4调节的RNA转录物。这些研究将为遗传学提供新的见解。 Npas 4控制的程序介导其对抑制性突触发育的影响， 哺乳动物大脑中兴奋和抑制输入之间的平衡。这些研究报告将 对于我们理解自闭症谱系等认知功能障碍如何发挥作用至关重要 当微妙的兴奋/抑制平衡被破坏时，可能出现紊乱，并且可能提示治疗这些疾病的靶点。