Role of MEF2 and neural activity in cortical synaptic weakening and elimination

MEF2 和神经活动在皮质突触减弱和消除中的作用

• 批准号: 8653412
• 负责人: KIMBERLY M. HUBER
• 金额: $ 41.54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-08 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653412
• 关键词: Action Potentials; Address; Adult; Affect; Autistic Disorder; Biological Assay; Biological Neural Networks; Brain; Cells; Cognition; Cognition Disorders; Complex; Data; Dendritic Spines; Development; Electric Stimulation; Environment; Epilepsy; Etiology; Excitatory Synapse; FMR1; Family; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Expression; Genes; Genetic; Genetic Programming; Genetic Transcription; Grant; Hippocampus (Brain); Human; Human Genetics; Impaired cognition; Inherited; Intellectual functioning disability; Knowledge; Lead; Learning; Link; Long-Term Depression; Measures; Mediating; Memory; Mental Retardation; Messenger RNA; Metabotropic Glutamate Receptors; Molecular; Mus; Neocortex; Neurodevelopmental Disorder; Neurons; Pathway interactions; Pattern; Perception; Phenotype; Physiological; Play; Population; Process; Prosencephalon; Protein Isoforms; Proteins; Publishing; RNA-Binding Proteins; Role; Sensory; Slice; Structure; Synapses; Synaptic plasticity; Testing; Transcript; Translations; Vertebral column; Work; base; cognitive function; disability; experience; in vitro Model; in vivo; loss of function mutation; mouse model; muscle enhancer factor-2A; myocyte-specific enhancer-binding factor 2; neocortical; neural circuit; new therapeutic target; novel; optogenetics; postnatal; postsynaptic; programs; protein function; protocadherin 10; public health relevance; relating to nervous system; research study; synaptic function; synaptogenesis; transcription factor

Project Summary: Cortical structures (the hippocampus and neocortex) are critical for cognition and perception, and their improper function is implicated in intellectual disability and autism. The establishment of proper cortical circuits requires a complex interaction of neural activity and genetic programs that control the formation and elimination of specific synaptic connections. Studies of structural excitatory synapses, such as spines, find there is a rapid period of synaptogenesis early in postnatal development followed by a later period of elimination (or pruning) - in both humans and mice. Importantly, sensory experience and circuit activity drives the pruning of spines in vivo. Spine elimination is also triggered by learning in adults and may mediate the refinement of circuits that maintain memories. However, spines are an indirect measure of synaptic number and provide little information about how pruning regulates synaptic function and connectivity of specific cortical pathways. Furthermore, virtually nothing is known of the cellular and molecular mechanisms of activity and sensory experience-dependent synapse elimination in cortical neurons. Using assays of synaptic function in isolated cortical pathways, we have accumulated evidence indicating that activity-dependent synaptic pruning is regulated by the activation of the Myocyte-Enhancer Factor 2 (MEF2) family of transcription factors. We find that the RNA binding protein, Fragile X Mental Retardation Protein (FMRP) is required for MEF2- triggered synapse elimination by regulating the translation of MEF2-generated transcripts - including Protocadherin10 (Pcdh10) and Arc/Arg3.1. We find that Arc and Pcdh10 mediate elimination of synapses through distinct mechanisms. Importantly, loss of function mutations in MEF2C, FMRP and Pcdh10 are linked to intellectual disability (ID), autism and circuit hyperexcitability. Little is known of the physiological and in vivo conditions that lead to elimination of functional synaptic connections on cortical neurons and if or how this involves MEF2c, FMRP, Pcdh10, and Arc. In Aim 1 we will use optogenetics to induce physiological patterns of CA1 neuron firing and synapse elimination to determine the role of MEF2 isoforms, Fmr1 and Pcdh10 in physiological activity-dependent synapse elimination. In Aim 2 we will determine if endogenous MEF2 isoforms contribute to developmental pruning of functional excitatory synaptic connections onto cortical neurons in vivo. We also have new data suggesting that a novel experience activates MEF2-dependent Arc transcription which primes CA1 neurons for long-term synaptic depression upon activation of metabotropic glutamate receptors (mGluR-LTD). Novelty-priming of mGluR-LTD may be a precursor to synapse elimination and contribute to the formation of sparse cortical network representations of memories. In Aim 3 we propose to determine if MEF2 contributes to novelty-induced gene expression, priming of mGluR-LTD, and novelty habituation. In Aim 4 we will use optogenetics and electrical stimulation to establish an in vitro model of novelty-induced priming of LTD to reveal cellular mechanisms.

项目概述：皮层结构（海马体和新皮层）对认知和行为至关重要