Dysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids
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.
Authors
- Michael G. Rosenfeld (ORCID: https://orcid.org/0000-0002-1572-156X)
- Melissa Luevanos
- Agnes P. Chan (ORCID: https://orcid.org/0000-0003-2373-9580)
- Emily Schahrer (ORCID: https://orcid.org/0000-0002-7375-9822)
- Titas Grabauskas (ORCID: https://orcid.org/0000-0002-3512-9862)
- Abdullah Sultan (ORCID: https://orcid.org/0000-0001-8203-4391)
- Daniel H. Geschwind (ORCID: https://orcid.org/0000-0003-2896-3450)
- Piotr Koźbiał
- Shing Fai Chan
- Ivan García-Bassets (ORCID: https://orcid.org/0000-0002-6941-9585)
- Swagata Ghatak (ORCID: https://orcid.org/0000-0001-5462-401X)
- Michael Bula (ORCID: https://orcid.org/0000-0002-2164-0619)
- Kevin Lopez (ORCID: https://orcid.org/0000-0003-0322-087X)
- Maria Talantova (ORCID: https://orcid.org/0000-0002-6460-1302)
- Riki Kawaguchi (ORCID: https://orcid.org/0000-0002-2489-4825)
- Stuart A. Lipton (ORCID: https://orcid.org/0000-0002-3490-1259)
- Nima Dolatabadi
- Dorit Trudler
- Rajesh Ambasudhan (ORCID: https://orcid.org/0000-0002-9575-5961)
- Paweł Stankiewicz (ORCID: https://orcid.org/0000-0002-6456-7490)
- Nicholas J. Schork (ORCID: https://orcid.org/0000-0003-0920-5013)
- Parth Patel (ORCID: https://orcid.org/0000-0001-5207-2776)
- Sergio R. Labra (ORCID: https://orcid.org/0000-0002-4072-1131)
- Sarah Moore Noveral
- Mayu Teranaka (ORCID: https://orcid.org/0000-0002-4589-3370)
- Wei Lin (ORCID: https://orcid.org/0009-0006-5068-4502)
- James Parker (ORCID: https://orcid.org/0000-0002-1150-8374)
- Yongwook Choi
- Nobuki Nakanishi
- Clare Bakker
Institutions
- Scripps Research Institute (US)
- Translational Genomics Research Institute (US)
- Howard Hughes Medical Institute (US)
- University of Indianapolis (US)
- University of California, Los Angeles (US)
- National Institute of Science Education and Research (IN)
- Baylor College of Medicine (US)
- Discovery Institute (US)
- University of California System (US)
- University of California San Diego (US)
- Scintillon Institute (US)
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1038/s41380-024-02761-9
- Citations
- 11
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 6.05
Funders
- Autism Speaks
- California Institute for Regenerative Medicine
- National Institutes of Health