Kris Loerwald, Genevieve Konopka, Gemma Molinaro, Aram J. Raissi, Jaswinder Kumar, Stefano Berto, Kacey Rajkovich, Jonathan Raduazzo, Adam J Harrington, Yuhong Guo, Christopher W. Cowan, and Kimberly M. Huber
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. DOI: http://dx.doi.org/10.7554/eLife.20059.001, eLife digest Abnormal development of the brain contributes to intellectual disability, as well as to a number of psychiatric disorders, including schizophrenia and autism. As the brain develops, neurons establish connections with one another called synapses, which are either excitatory or inhibitory. At excitatory synapses, an electrical signal in the first cell increases the likelihood that the second cell will also produce an electrical signal. At inhibitory synapses, electrical activity in the first cell reduces the chances of the second cell producing an electrical signal. An imbalance between excitatory and inhibitory activity is one of the factors thought to give rise to neurodevelopmental disorders. Many individuals with schizophrenia, autism or intellectual disability possess mutations in, or near, a gene called MEF2C. This gene, which is active in both excitatory and inhibitory neurons, encodes a protein that regulates the activity of many other genes during brain development. Harrington, Raissi et al. therefore hypothesized that alterations in MEF2C might predispose individuals to neurodevelopmental disorders by disrupting the balance of excitatory and inhibitory synapses in the developing brain. To test this idea, Harrington, Raissi et al. generated mice that lack the Mef2c gene in a large proportion of their neurons throughout development. As predicted, the animals showed an imbalance of excitatory and inhibitory synapses in the brain’s outer layer, the cortex. They also displayed changes in behavior like those seen in autism. These included a loss of interest in social interaction and a reduction in vocalizations, suggesting impaired communication. Other behavioral changes included hyperactivity, repetitive movements and severe learning impairments: all features commonly observed in human neurodevelopmental disorders. The next challenge is to understand when, where and how MEF2C acts in the cortex to shape the balance of excitatory and inhibitory connections. Once this is known, further studies can test whether disrupting these processes leads directly to behaviors characteristic of autism, schizophrenia and intellectual disability. This may lead to the development of new drugs that can reverse or improve the symptoms of these conditions in affected individuals. DOI: http://dx.doi.org/10.7554/eLife.20059.002