TY - JOUR
KW - Autism spectrum disorders
KW - Neuroscience
AU - Dorit Trudler
AU - Swagata Ghatak
AU - Michael Bula
AU - James Parker
AU - Maria Talantova
AU - Melissa Luevanos
AU - Sergio Labra
AU - Titas Grabauskas
AU - Sarah Moore Noveral
AU - Mayu Teranaka
AU - Emily Schahrer
AU - Nima Dolatabadi
AU - Clare Bakker
AU - Kevin Lopez
AU - Abdullah Sultan
AU - Parth Patel
AU - Agnes Chan
AU - Yongwook Choi
AU - Riki Kawaguchi
AU - Pawel Stankiewicz
AU - Ivan Garcia-Bassets
AU - Piotr Kozbial
AU - Michael G. Rosenfeld
AU - Nobuki Nakanishi
AU - Daniel H. Geschwind
AU - Shing Fai Chan
AU - Wei Lin
AU - Nicholas J. Schork
AU - Rajesh Ambasudhan
AU - Stuart A. Lipton
AB - MEF2C 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.
BT - Molecular Psychiatry
DA - 2024-09-30
DO - 10.1038/s41380-024-02761-9
LA - en
N2 - MEF2C 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.
PY - 2024
SP - 1
EP - 18
T2 - Molecular Psychiatry
TI - Dysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids
UR - https://www.nature.com/articles/s41380-024-02761-9
Y2 - 2024-12-09
SN - 1476-5578
ER -