Cited by 193Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

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

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Harrington, Adam J, Raissi, Aram, Rajkovich, Kacey, Berto, Stefano, Kumar, Jaswinder, Molinaro, Gemma, Raduazzo, Jonathan, Guo, Yuhong +4 more·2016·eLife

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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  • Animal models that mimic schizophrenia reproduce the loss of PV-INs in the hippocampus.

    “Animal models that mimic schizophrenia replicate the loss of PV-INs in the hippocampus [6,14,15], and show a loss of PV fluorescence per cell in prelimbic regions [16].”

    From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [15]

  • Clear emergence of Sst, Vip and Id2 subtypes was apparent for a subset of cells at E18.5, but Pvalb neurons could not be clearly subdivided by P10.

    “the clear emergence of Sst, Vip and Id2 subtypes was apparent for a subset of cells at E18.5 (Extended Data Figure 8), but we were unable to clearly subdivide Pvalb neurons by P10, in accordance with their late maturation28.”

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Authors
Harrington, A. J., Raissi, A., Rajkovich, K., Berto, S., Kumar, J., Molinaro, G., Raduazzo, J., Guo, Y., Loerwald, K., Konopka, G., Huber, K. M., & Cowan, C. W.
Affiliations
  • Harvard University (US)
  • The University of Texas Southwestern Medical Center (US)
  • Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
Corresponding author
Cowan, Christopher W
Venue
eLife
Published
2016-10-25
Volume
5
ISSN
2050-084X (ISSN-L)
OpenAlex
W2534955677
Cited by
193
References
72
Citations by year
2026: 11 · 2025: 31 · 2024: 29 · 2023: 12 · 2022: 18 · 2021: 18 · 2020: 34 · 2019: 18 · 2018: 12 · 2017: 10
FWCI
10.77
Type
journal article
Language
en
Open access
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (F32 HD078050, HD052731, OD010737, DA027664)
  • Simons Foundation (SFARI #206919)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
MEF2C, neurodevelopmental disorders, autism spectrum disorder, intellectual disability, schizophrenia, excitatory neurons, inhibitory neurons, synaptic transmission, cortical network activity, transcriptional repression, hippocampus, differential gene expression, autism-like behavior
MeSH terms
Animals, Autistic Disorder, Behavior, Animal, Cerebral Cortex, Hippocampus, Intellectual Disability, Synapses, Mice, Gene Knockdown Techniques, MEF2 Transcription Factors, Neurodevelopmental Disorders

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