MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders

Adam J. Harrington; Aram Raissi; Kacey Rajkovich; Stefano Berto; Jaswinder Kumar; Gemma Molinaro; Jonathan Raduazzo; Yuhong Guo; Kris Loerwald; Genevieve Konopka; Kimberly M. Huber; Christopher W. Cowan

doi:10.7554/eLife.20059

MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders

Adam J. Harrington, Aram Raissi, Kacey Rajkovich, Stefano Berto, Jaswinder Kumar, Gemma Molinaro, Jonathan Raduazzo, Yuhong Guo, Kris Loerwald, Genevieve Konopka, Kimberly M. Huber, Christopher W. Cowan

Research output: Contribution to journal › Article › peer-review

99 Scopus citations

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.

Original language	English (US)
Article number	e20059
Journal	eLife
Volume	5
Issue number	OCTOBER2016
DOIs	https://doi.org/10.7554/eLife.20059
State	Published - Oct 25 2016

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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title = "MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders",

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.",

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AU - Kumar, Jaswinder

AU - Molinaro, Gemma

AU - Raduazzo, Jonathan

AU - Guo, Yuhong

AU - Loerwald, Kris

AU - Konopka, Genevieve

AU - Huber, Kimberly M.

AU - Cowan, Christopher W.

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MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders

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