Hyperfunction of PSD-95 leads to hyperexcitability and cognitive abnormalities in MEF2C haploinsufficiency.

Myocyte enhancer factor 2C (MEF2C) is a transcription factor critical for brain circuit development and cognitive behavior. The loss of one copy of MEF2C leads to MEF2C haploinsufficiency syndrome (MCHS), a neurodevelopmental disorder characterized by intellectual disability, epilepsy, and behavioral phenotypes associated with autism spectrum disorders. Given that numerous genes are regulated by MEF2C, the neuronal and behavioral deficits in MCHS are complex, and there is currently no effective disease-modifying strategy for this disorder. Here, we show that MEF2C haploinsufficiency in forebrain excitability neurons led to an elevation of postsynaptic density protein 95 (PSD-95) in mice. This elevation of PSD-95 coincided with an increased number of structural synapses, facilitated surface expression of N-methyl-D-aspartate (NMDA) receptors, augmented neuronal excitability, and increased susceptibility to seizures. Knocking down PSD-95 or inhibiting the interaction between PSD-95 and NMDA receptors efficiently reduced hyperexcitability phenotypes in MEF2C haploinsufficiency. Most importantly, knocking down PSD-95 significantly improved cognitive behaviors in mice with MEF2C haploinsufficiency. In summary, our study revealed a mechanism underlying hyperexcitability and cognitive defects associated with MCHS and suggests PSD-95 as a therapeutic target for MCHS.