MEF2C hypofunction in GABAergic cells alters neurotypical behavior and prefrontal cortex inhibitory synaptic transmission in a sex-dependent manner

Heterozygous loss-of-function mutations or deletions of the MEF2C gene cause a neurodevelopmental disorder, termed MEF2C Haploinsufficiency syndrome (MCHS), that is characterized by autism spectrum disorder, intellectual disability, seizures, and other neurological symptoms. In mice, global Mef2c heterozygosity produces numerous behavioral phenotypes reminiscent of MCHS. MEF2C is highly expressed in multiple cell populations in the developing brain, including GABAergic inhibitory neurons. While MEF2C hypofunction in excitatory neurons or microglia alter neurotypical behaviors and brain circuit function, the impact of MEF2C heterozygosity in GABAergic neurons remains unknown. Overall design: We employed GABAergic cell type-specific manipulations to study mouse Mef2c heterozygosity in a battery of MCHS-like behaviors. We also performed single cell transcriptomics and patch-clamp electrophysiology and optogenetics to assess intrinsic excitability and synaptic transmission.