Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.387639v1?rss=1 Authors: Trudler, D., Ghatak, S., Parker, J., Talantova, M., Grabauskas, T., Noveral, S. M., Teranaka, M., Luevanos, M., Dolatabadi, N., Bakker, C., Lopez, K., Sultan, A., Chan, A., Choi, Y., Kawaguchi, R., Schork, N., Stankiewicz, P., Garcia-Bassets, I., Kozbial, P., Rosenfeld, M. G., Nakanishi, N., Geschwind, D., Chan, S. F., Ambasudhan, R., Lipton, S. A. 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. Copy rights belong to original authors. Visit the link for more info