Analysis of MEF2 in Cortical Connectivity and Autism-Associated Behaviors

MEF2 在皮质连接和自闭症相关行为中的分析

• 批准号: 8594680
• 负责人: ADAM JOHN HARRINGTON
• 金额: $ 4.92万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594680
• 关键词: AMPA Receptors; Adult; Anxiety; Architecture; Autistic Disorder; Behavior; Behavioral; Brain; Candidate Disease Gene; Cell physiology; Cells; Cerebral cortex; Complex; Cytoskeletal Proteins; Defect; Dendritic Spines; Development; Disease; Excitatory Synapse; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Silencing; Gene Targeting; Genes; Genetic; Glutamates; Hippocampus (Brain); Human; Human Genetics; Hyperactive behavior; Individual; Inherited; Knockout Mice; Link; Mental Retardation; Messenger RNA; Molecular; Mus; Muscle Cells; National Research Service Awards; Neurobiology; Neurocognitive; Neurodevelopmental Disorder; Neurons; Patients; Phenotype; Process; Prosencephalon; Protein Binding; Proteins; RNA Binding; RNA-Binding Proteins; Regulation; Relative (related person); Reporting; Role; Series; Social Behavior; Staging; Staining method; Stains; Synapses; Tamoxifen; Techniques; Testing; Transgenic Mice; autism spectrum disorder; base; communication behavior; density; enhancing factor; excitatory neuron; gene function; in vivo; knockout animal; learned behavior; loss of function; mouse model; muscle enhancer factor-2A; myocyte-specific enhancer-binding factor 2; nervous system disorder; neural circuit; neuron development; neuronal circuitry; neuronal survival; protocadherin 10; public health relevance; recombinase; research study; response; social communication; synaptic function; synaptogenesis; transcription factor; vocalization

DESCRIPTION (provided by applicant): Proper establishment of neuronal circuitry during brain development involves a complex interplay between cellular/molecular processes and neuronal activity that promote the formation of new synapses and elimination of inappropriate synapses. Defects in such processes to control synapse number can result in neurocognitive disorders, including mental retardation and autism spectrum disorders (ASDs). Individuals with autism and a mouse model of Fragile X Syndrome (FXS), the most prevalent inherited form of autism, display increased dendritic spine density in cortical neurons. Many autism-related genes function in regulating proper synapse formation and elimination; therefore, characterizing the cellular mechanisms involved in synapse regulation remains a critical step to understanding autism-spectrum disorders. The transcription factors myocyte enhancer factor 2 (MEF2 A-D) function in developing and adult brains to regulate excitatory synapse elimination in response to neuronal activity. Our lab recently found that MEF2-induced synapse elimination requires the RNA-binding protein, Fragile X Mental Retardation Protein (FMRP), strongly suggesting that deficits in MEF2/FMRP-dependent functional synapse elimination likely contribute to the cortical connectivity abnormalities and behavioral deficits observed in FXS and autism. In preliminary studies using conditional forebrain MEF2 knockout mice, I observe a number of behavioral abnormalities reminiscent of FXS and autism phenotypes in humans. In this NRSA proposal, we outline a series of cutting-edge studies to closely examine the role of MEF2 genes in autism core domain behaviors, and to assess the roles of MEF2 genes and a MEF2 target gene, Arc, in the proper establishment of structural synaptic connectivity in the developing cortex. With synapse elimination defects observed in autism and FXS, we believe that our studies will significantly enhance our understanding of the neurobiology in these complex diseases.

描述（由申请人提供）：在大脑发育过程中正确建立神经元电路涉及细胞/分子过程与神经元活动之间的复杂相互作用，从而促进形成新的突触并消除不适当的突触。在此类过程中控制突触数的缺陷可能导致神经认知障碍，包括智力低下和自闭症谱系障碍（ASDS）。具有自闭症的个体和脆弱X综合征的小鼠模型（FXS）是自闭症的最普遍的遗传形式，在皮质神经元中显示出增加的树突状脊柱密度。许多与自闭症相关的基因在调节适当的突触形成和消除方面发挥作用；因此，表征突触调节涉及的细胞机制仍然是理解自闭症谱系障碍的关键步骤。转录因子在发育和成年大脑中的心肌细胞增强因子2（MEF2 A-D）功能，以调节响应神经元活性的兴奋性突触消除。我们的实验室最近发现，MEF2诱导的突触消除需要RNA结合蛋白，脆弱的X智力低下蛋白（FMRP），这强烈表明MEF2/FMRP依赖性功能突触消除的缺陷可能有助于在FXS中观察到皮层连通性异常和行为缺陷。在使用条件前脑MEF2基因敲除小鼠的初步研究中，我观察到许多行为异常，让人联想到人类FXS和自闭症表型。在此NRSA提案中，我们概述了一系列尖端研究，以仔细研究MEF2基因在自闭症核心结构域行为中的作用，并评估MEF2基因和MEF2靶基因ARC的作用，ARC在适当地建立发育中的Cortex中结构突触连接。随着自闭症和FXS中观察到的突触消除缺陷，我们认为我们的研究将显着增强我们对这些复杂疾病中神经生物学的理解。