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Transcriptional control of inhibitory synapse formation

抑制性突触形成的转录控制

基本信息

批准号：
8380638
负责人：
MICHAEL ELDON GREENBERG
金额：
$ 29.78万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
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/8380638
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

项目摘要

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，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。我们的实验室发现了bHLH转录因子Npas4在抑制性突触在兴奋性神经元上的发育过程中的作用，以及对抑制性突触和兴奋性突触之间平衡的影响。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缺失在发育过程中不同时期对抑制性突触形成和功能的影响。我们也将使用这个鼠标