Abstract
MEF2C has been shown to be a critical transcription factor for neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Here, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found an aberrant micro-RNA-mediated gliogenesis pathway that contributes to decreased neurogenesis. We also demonstrate network-level hyperexcitability in neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the extrasynaptic NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks suggesting that our approach may lead to personalized therapy for multiple forms of ASD.
One sentence summary Autism-like MEF2C+/- patient hiPSC models show miRNA-mediated overproduction of astrocytes and hyperactivity of neurons.
Competing Interest Statement
The authors declare that S.A.L. is an inventor on worldwide patents for the use of memantine and NitroSynapsin for neurodegenerative and neurodevelopmental disorders. Per Harvard University guidelines, S.A.L. participates in a royalty-sharing agreement with his former institution Boston Childrens Hospital/Harvard Medical School, which licensed the drug memantine (Namenda) to Forest Laboratories/Actavis/Allergan/AbbVie, Inc. NitroSynapsin is licensed to EuMentis Therapeutics, Inc. The other authors declare no financial conflicts of interest.