A typical neocortical pyramidal neuron integrates information from thousands of excitatory inputs from both ?local? circuits, within a cortical region, and from many ?long-range? circuits from other cortical and non-cortical regions, both ipsi- and contralaterally. These long-range connections develop postnatally, are highly specified, and regulated by sensory experience. Remarkably, >50% of excitatory synapses a typical neocortical pyramidal neuron receives are from long-range connections, but virtually nothing is known of how functional long-range connections develop, are regulated by experience or if and how long-range and local inputs are balanced. In the last grant cycle, we discovered that the activity-dependent transcription factor, Myocyte-Enhancer Factor 2C (MEF2C) functions postnatally and cell autonomously to regulate the balance of local and long-range excitatory connectivity onto layer (L) 2/3 neocortical neurons in primary somatosensory cortex. Specifically, MEF2C promotes connectivity from multiple local excitatory circuits onto L2/3 neurons, while weakening callosal inputs from contralateral somatosensory cortex. Importantly, sensory experience is necessary for MEF2C regulation of both local and callosal circuits suggesting that MEF2C as a key player in experience-dependent, input-specific development of cortical circuits. Our findings have important implications for neurodevelopmental disorders. Brain mapping studies in humans with autism spectrum disorder (ASD) and schizophrenia (SCZ) reveal imbalances in local vs. long-range functional cortical connectivity. Furthermore, loss of function mutations in Mef2c are linked with intellectual disability (ID), ASD, epilepsy and SCZ in humans and mice. We hypothesize that sensory experience-driven neural activity regulates MEF2C-dependent transcriptional control of target genes to mediate input-specific development and plasticity of cortical circuits. Thus, a corollary of this hypothesis predicts that loss of function mutations in Mef2c or its effectors would result in imbalances of local and long-range connectivity, abnormal sensory-related behaviors and neuropsychiatric disease. To test these hypotheses:
In Aim 1, we will use state-of-the-art optogenetic and photostimulation circuit mapping methods to determine if Mef2c deletion generally strengthens long-range inputs onto L2/3 neurons, bidirectionally regulates inputs based on their dendritic location and maintains the input-specificity of mature circuits.
Aim 2 : MEF2C functions both to repress transcription of target genes and stimulate their transcription in response to neural activity. Using MEF2C mutants, we will determine which of these functions mediates experience-dependent, input-specific regulation of cortical circuits.
Aim 3 : FMRP, mGluR5 and Arc are required for MEF2 regulation of synapses in culture neurons and associated with ASD, ID and SCZ. Here, we will test their role in MEF2C-mediated input-specific development of cortical circuits.
Aim 4 : To identify candidate genes that regulate cortical circuit input specificity, we will identify the postnatal MEF2C- and experience-dependent transcriptomes in L2/3 neocortical neurons using fluorescent-activated cell sorting (FACS) and RNA sequencing.
In response to experience, neurons form specific connections locally, within a brain region, and long-range connections, with neurons from diverse brain regions and the balance of local and long-range connections is abnormal in neurodevelopmental disorders. We have identified a gene, MEF2C, which is mutated in autism and schizophrenia and regulated by experience, that differentially affects local and long-range connections; the first of its kind. In this grant application, we will determine how MEF2C and experience determine the specific connectivity of local and long-range connections to understand normal brain development and neurodevelopmental disorders.
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