02591nas a2200517   4500000000100000000000100001008004100002260001500043653003000058653001700088100001800105700001900123700001700142700001700159700002000176700002100196700001700217700002100234700002400255700001800279700001900297700002000316700001700336700001600353700002000369700001600389700001500405700001800420700001900438700002200457700002400479700001800503700002500521700002100546700002400567700001900591700001200610700002300622700002200645700002100667245011400688856005500802300000900857520119300866022001402059       2024                            d  c2024-09-3010aAutism spectrum disorders10aNeuroscience1 aDorit Trudler1 aSwagata Ghatak1 aMichael Bula1 aJames Parker1 aMaria Talantova1 aMelissa Luevanos1 aSergio Labra1 aTitas Grabauskas1 aSarah Moore Noveral1 aMayu Teranaka1 aEmily Schahrer1 aNima Dolatabadi1 aClare Bakker1 aKevin Lopez1 aAbdullah Sultan1 aParth Patel1 aAgnes Chan1 aYongwook Choi1 aRiki Kawaguchi1 aPawel Stankiewicz1 aIvan Garcia-Bassets1 aPiotr Kozbial1 aMichael G. Rosenfeld1 aNobuki Nakanishi1 aDaniel H. Geschwind1 aShing Fai Chan1 aWei Lin1 aNicholas J. Schork1 aRajesh Ambasudhan1 aStuart A. Lipton00aDysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids  uhttps://www.nature.com/articles/s41380-024-02761-9  a1-183 aMEF2C is a critical transcription factor in 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). Despite prior animal studies of MEF2C heterozygosity to mimic MHS, MHS-specific mutations have not been investigated previously, particularly in a human context as hiPSCs afford. Here, for the first time, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found that decreased neurogenesis was accompanied by activation of a micro-(mi)RNA-mediated gliogenesis pathway. We also demonstrate network-level hyperexcitability in MHS neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the predominantly extrasynaptic (e)NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks, suggesting that treatment of MHS deficits may possibly help other forms of ASD as well.  a1476-5578