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

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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 languageEnglish (US)
Article numbere20059
JournaleLife
Volume5
Issue numberOCTOBER2016
DOIs
Publication statusPublished - Oct 25 2016

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Harrington, A. J., Raissi, A., Rajkovich, K., Berto, S., Kumar, J., Molinaro, G., ... Cowan, C. W. (2016). MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. eLife, 5(OCTOBER2016), [e20059]. https://doi.org/10.7554/eLife.20059