# Transcriptional Regulation of Synapse Development in Intellectual and Developmental Disorders

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $373,750

## Abstract

Project Summary/Abstract
 Autism Spectrum Disorders (ASDs) are thought to result from in brain synapse dysfunction. Mutations or
deletions of the MEF2C gene have been linked recently to several neurodevelopmental disorders, including
autism, intellectual disability (ID) and schizophrenia (SCZ). Mef2 transcription factors promote activity-
dependent, glutamatergic synapse elimination – a possible dysregulated process in autism. We find that Mef2c
conditional forebrain knockout (Mef2c cKO) mice display behavioral abnormalities similar to the 3 core features
used to diagnose autism in humans, including abnormalities in communication, social interaction, and repetitive
motor behaviors. Surprisingly, we observed a significant increase in inhibitory (GABAergic) and a decrease in
excitatory (glutamatergic) synapse density and strength, which suggests the hypothesis that Mef2c
functions as an activity-regulated transcriptional repressor to control the balance of inhibitory and
excitatory synapses in developing cortical neurons. Loss of Mef2c repressor function promotes excitatory
synapse elimination and increases inhibitory synapse density, which results in numerous behaviors with
potential relevance to autism, ID and SCZ. In this revised grant proposal, we seek to extend our extensive
preliminary findings to explore the role and regulation of Mef2c in cortical synapse development and in
behaviors associated with intellectual and developmental disabilities.
 Aim 1. In this aim, we will use well-established behavioral assays in the lab to analyze social interaction,
communication, repetitive behaviors, reward, anxiety, and learning and memory tests in Mef2c cKO mice.
 Aim 2. In this aim, we will take a multi-pronged approach in culture and in vivo to analyze the role of Mef2c
in the regulation of excitatory and inhibitory synapse density and function. We will test the hypothesis that
Mef2c functions cell-autonomously as a transcriptional repressor to regulate glutamatergic synapse elimination
and GABAergic synapse formation/stabilization, and it does so in an activity-dependent, homeostatic, negative
feedback mechanism that promotes inhibition and reduces excitation.
 Aim 3. In this aim, we will extend our preliminary findings with HTS-CLIP and RNA-seq to assess the role
of Pcdh17, an newly identified common MEF2/FMRP target gene, in Mef2c-induced excitatory synapse
elimination and inhibitory synapse formation in cortical pyramidal neurons in culture and in vivo.

## Key facts

- **NIH application ID:** 9929649
- **Project number:** 5R01MH111464-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Christopher W Cowan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,750
- **Award type:** 5
- **Project period:** 2017-08-10 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929649

## Citation

> US National Institutes of Health, RePORTER application 9929649, Transcriptional Regulation of Synapse Development in Intellectual and Developmental Disorders (5R01MH111464-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9929649. Licensed CC0.

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