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
Affiliations
Adam J Harrington
Department of Neurosciences, Medical University of South Carolina, Charleston, United States; Department of Psychiatry, Harvard Medical School, Belmont, United States
Aram Raissi
Department of Psychiatry, Harvard Medical School, Belmont, United States
Kacey Rajkovich
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
Stefano Berto
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
Jaswinder Kumar
Department of Psychiatry, Harvard Medical School, Belmont, United States; Medical Scientist Training Program, The University of Texas Southwestern Medical Center, Dallas, United States
Gemma Molinaro
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
Jonathan Raduazzo
Department of Psychiatry, Harvard Medical School, Belmont, United States
Yuhong Guo
Department of Psychiatry, Harvard Medical School, Belmont, United States
Kris Loerwald
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
Genevieve Konopka
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
Kimberly M Huber
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
Department of Neurosciences, Medical University of South Carolina, Charleston, United States; Department of Psychiatry, Harvard Medical School, Belmont, United States
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.
