# Regulation of experience-dependent cortical circuit development by MEF2C and genes linked to neurodevelopmental disorders

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $449,052

## Abstract

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 co...

## Key facts

- **NIH application ID:** 9869760
- **Project number:** 5R01HD052731-13
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jay Robert Gibson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,052
- **Award type:** 5
- **Project period:** 2008-02-08 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869760

## Citation

> US National Institutes of Health, RePORTER application 9869760, Regulation of experience-dependent cortical circuit development by MEF2C and genes linked to neurodevelopmental disorders (5R01HD052731-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869760. Licensed CC0.

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