@article{4811,
  keywords = {Autism spectrum disorders, Neuroscience},
  author = {Dorit Trudler and Swagata Ghatak and Michael Bula and James Parker and Maria Talantova and Melissa Luevanos and Sergio Labra and Titas Grabauskas and Sarah Moore Noveral and Mayu Teranaka and Emily Schahrer and Nima Dolatabadi and Clare Bakker and Kevin Lopez and Abdullah Sultan and Parth Patel and Agnes Chan and Yongwook Choi and Riki Kawaguchi and Pawel Stankiewicz and Ivan Garcia-Bassets and Piotr Kozbial and Michael G. Rosenfeld and Nobuki Nakanishi and Daniel H. Geschwind and Shing Fai Chan and Wei Lin and Nicholas J. Schork and Rajesh Ambasudhan and Stuart A. Lipton},
  title = {Dysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids},
  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.},
  year = {2024},
  journal = {Molecular Psychiatry},
  pages = {1-18},
  month = {2024-09-30},
  issn = {1476-5578},
  url = {https://www.nature.com/articles/s41380-024-02761-9},
  doi = {10.1038/s41380-024-02761-9},
  language = {en},
}