MEF2C Regulates Cortical Inhibitory and Excitatory Synapses and Behaviors Relevant to Neurodevelopmental Disorders

Overview

Journal Elife

Specialty Biology

Date 2016 Nov 4

PMID 27779093

Citations 84

Authors

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

Affiliations

Soon will be listed here.

Abstract

Numerous genetic variants associated with 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 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 mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the 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.

Citing Articles

Establishing a Mouse Model of NL3R617W-Associated Autism Spectrum Disorder for a Functional Study.

Gao W, Cai Q, Ying X, Zhao B Actas Esp Psiquiatr. 2025; 53(2):253-266.

PMID: 40071366 PMC: 11898267. DOI: 10.62641/aep.v53i2.1780.

Editorial: Cellular and molecular mechanisms that govern assembly, plasticity, and function of GABAergic inhibitory circuits in the mammalian brain.

Hayano Y, Miyoshi G, Paul A, Taniguchi H Front Cell Neurosci. 2025; 19:1568845.

PMID: 40007758 PMC: 11850328. DOI: 10.3389/fncel.2025.1568845.

Massively parallel assessment of gene regulatory activity at human cortical structure associated variants.

Matoba N, McAfee J, Krupa O, Bell J, Le B, Valone J bioRxiv. 2025; .

PMID: 39974944 PMC: 11839127. DOI: 10.1101/2025.02.08.635393.

Topological identification and interpretation for single-cell epigenetic regulation elucidation in multi-tasks using scAGDE.

Hao G, Fan Y, Yu Z, Su Y, Zhu H, Wang F Nat Commun. 2025; 16(1):1691.

PMID: 39956806 PMC: 11830825. DOI: 10.1038/s41467-025-57027-x.

Sleep need driven oscillation of glutamate synaptic phenotype.

Vogt K, Kulkarni A, Pandi R, Pandey R, Dehnad M, Konopka G Elife. 2025; 13.

PMID: 39950545 PMC: 11828481. DOI: 10.7554/eLife.98280.

References

Pirooznia M, Wang T, Avramopoulos D, Valle D, Thomas G, Huganir R . SynaptomeDB: an ontology-based knowledgebase for synaptic genes. Bioinformatics. 2012; 28(6):897-9. PMC: 3307115. DOI: 10.1093/bioinformatics/bts040. View

Lubs H, Stevenson R, Schwartz C . Fragile X and X-linked intellectual disability: four decades of discovery. Am J Hum Genet. 2012; 90(4):579-90. PMC: 3322227. DOI: 10.1016/j.ajhg.2012.02.018. View

Pulipparacharuvil S, Renthal W, Hale C, Taniguchi M, Xiao G, Kumar A . Cocaine regulates MEF2 to control synaptic and behavioral plasticity. Neuron. 2008; 59(4):621-33. PMC: 2626175. DOI: 10.1016/j.neuron.2008.06.020. View

Mikhail F, Lose E, Robin N, Descartes M, Rutledge K, Rutledge S . Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. Am J Med Genet A. 2011; 155A(10):2386-96. DOI: 10.1002/ajmg.a.34177. View

Wilkerson J, Tsai N, Maksimova M, Wu H, Cabalo N, Loerwald K . A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination. Cell Rep. 2014; 7(5):1589-1600. PMC: 4057996. DOI: 10.1016/j.celrep.2014.04.035. View

Leifer D, Krainc D, Yu Y, McDermott J, Breitbart R, Heng J . MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex. Proc Natl Acad Sci U S A. 1993; 90(4):1546-50. PMC: 45911. DOI: 10.1073/pnas.90.4.1546. View

Mortazavi A, Williams B, McCue K, Schaeffer L, Wold B . Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008; 5(7):621-8. DOI: 10.1038/nmeth.1226. View

Insel T . Is social attachment an addictive disorder?. Physiol Behav. 2003; 79(3):351-7. DOI: 10.1016/s0031-9384(03)00148-3. View

Tsai N, Wilkerson J, Guo W, Maksimova M, DeMartino G, Cowan C . Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell. 2012; 151(7):1581-94. PMC: 3530171. DOI: 10.1016/j.cell.2012.11.040. View

10.

McKinsey T, Zhang C, Olson E . MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci. 2002; 27(1):40-7. DOI: 10.1016/s0968-0004(01)02031-x. View

11.

Beaudoin 3rd G, Lee S, Singh D, Yuan Y, Ng Y, Reichardt L . Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat Protoc. 2012; 7(9):1741-54. DOI: 10.1038/nprot.2012.099. View

12.

Leifer D, Li Y, Wehr K . Myocyte-specific enhancer binding factor 2C expression in fetal mouse brain development. J Mol Neurosci. 1997; 8(2):131-43. DOI: 10.1007/BF02736778. View

13.

Adachi M, Lin P, Pranav H, Monteggia L . Postnatal Loss of Mef2c Results in Dissociation of Effects on Synapse Number and Learning and Memory. Biol Psychiatry. 2015; 80(2):140-148. PMC: 4826326. DOI: 10.1016/j.biopsych.2015.09.018. View

14.

Pfeiffer B, Zang T, Wilkerson J, Taniguchi M, Maksimova M, Smith L . Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron. 2010; 66(2):191-7. PMC: 2864778. DOI: 10.1016/j.neuron.2010.03.017. View

15.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

16.

Wehner J, Radcliffe R . Cued and contextual fear conditioning in mice. Curr Protoc Neurosci. 2008; Chapter 8:Unit 8.5C. DOI: 10.1002/0471142301.ns0805cs27. View

17.

Wang D, Kriegstein A . GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J Neurosci. 2008; 28(21):5547-58. PMC: 2684685. DOI: 10.1523/JNEUROSCI.5599-07.2008. View

18.

McCarthy S, Gillis J, Kramer M, Lihm J, Yoon S, Berstein Y . De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mol Psychiatry. 2014; 19(6):652-8. PMC: 4031262. DOI: 10.1038/mp.2014.29. View

19.

Rubenstein J . Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder. Curr Opin Neurol. 2010; 23(2):118-23. DOI: 10.1097/WCO.0b013e328336eb13. View

20.

Dichter G, Richey J, Rittenberg A, Sabatino A, Bodfish J . Reward circuitry function in autism during face anticipation and outcomes. J Autism Dev Disord. 2011; 42(2):147-60. PMC: 8624275. DOI: 10.1007/s10803-011-1221-1. View