MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders
- Medical University of South Carolina, United States
- Harvard Medical School, United States
- The University of Texas Southwestern Medical Center, United States
Abstract
Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) - a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice.
Data availability
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MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disordersPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE87202).
Article and author information
Author details
Christopher W Cowan
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Adam J Harrington
Simons Foundation (SFARI #206919)
- Kimberly M Huber
- Christopher W Cowan
National Institute on Drug Abuse
- Christopher W Cowan
NIH Office of the Director
- Kimberly M Huber
National Institutes of Health (F32 HD078050)
- Adam J Harrington
National Institutes of Health (DA027664)
- Christopher W Cowan
National Institutes of Health (HD052731)
- Kimberly M Huber
National Institutes of Health (OD010737)
- Christopher W Cowan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Christian Rosenmund, Charité-Universitätsmedizin Berlin, Germany
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the NIH. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2015N000178 and #2015N000160) of McLean Hospital.
Version history
- Received: July 26, 2016
- Accepted: October 11, 2016
- Accepted Manuscript published: October 25, 2016 (version 1)
- Version of Record published: November 3, 2016 (version 2)
- Version of Record updated: June 27, 2017 (version 3)
Copyright
© 2016, Harrington et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders
eLife 5:e20059.
https://doi.org/10.7554/eLife.20059
Further reading
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Accurate tracking of the same neurons across multiple days is crucial for studying changes in neuronal activity during learning and adaptation. Advances in high-density extracellular electrophysiology recording probes, such as Neuropixels, provide a promising avenue to accomplish this goal. Identifying the same neurons in multiple recordings is, however, complicated by non-rigid movement of the tissue relative to the recording sites (drift) and loss of signal from some neurons. Here, we propose a neuron tracking method that can identify the same cells independent of firing statistics, that are used by most existing methods. Our method is based on between-day non-rigid alignment of spike-sorted clusters. We verified the same cell identity in mice using measured visual receptive fields. This method succeeds on datasets separated from 1 to 47 days, with an 84% average recovery rate.
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Subpopulations of neurons in the subthalamic nucleus have distinct activity patterns that relate to the three hypotheses of the Drift Diffusion Model.
