Language
English
Publication Date
4-1-2025
Journal
Molecular Psychiatry
DOI
10.1038/s41380-024-02761-9
PMID
39349966
PMCID
PMC11919750
PubMedCentral® Posted Date
9-30-2024
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Humans, Organoids, Induced Pluripotent Stem Cells, MEF2 Transcription Factors, Neurons, Neurogenesis, MicroRNAs, Autism Spectrum Disorder, Autistic Disorder, Mutation, Haploinsufficiency, Neuroscience, Autism spectrum disorders
Published Open-Access
yes
Recommended Citation
Trudler, Dorit; Ghatak, Swagata; Bula, Michael; et al., "Dysregulation of miRNA Expression and Excitation in MEF2C Autism Patient hiPSC-Neurons and Cerebral Organoids" (2025). Faculty, Staff and Students Publications. 6404.
https://digitalcommons.library.tmc.edu/baylor_docs/6404