Dysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
30 Sep 2024
30 Sep 2024
Historique:
received:
11
01
2024
accepted:
20
09
2024
revised:
13
09
2024
medline:
1
10
2024
pubmed:
1
10
2024
entrez:
30
9
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 39349966
doi: 10.1038/s41380-024-02761-9
pii: 10.1038/s41380-024-02761-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIA NIH HHS
ID : R35 AG071734
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057409
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056259
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA048882
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS086890
Pays : United States
Organisme : NIDA NIH HHS
ID : DP1 DA041722
Pays : United States
Organisme : California Institute for Regenerative Medicine (CIRM)
ID : DISC2-11070
Organisme : Autism Speaks (Autism Speaks Inc.)
ID : postdoctoral fellowship grant #11721
Informations de copyright
© 2024. The Author(s).
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