Aberrant gliogenesis and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids
user-5f8cf7e04c775ec6fa691c92(2020)
摘要
MEF2C has been shown to be a critical transcription factor for 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). Here, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found an aberrant micro-RNA-mediated gliogenesis pathway that contributes to decreased neurogenesis. We also demonstrate network-level hyperexcitability in neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the extrasynaptic NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks suggesting that our approach may lead to personalized therapy for multiple forms of ASD.
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关键词
Neurogenesis,Gliogenesis,Haploinsufficiency,Autism,MEF2C,Autism spectrum disorder,Inhibitory postsynaptic potential,NMDA receptor,Neuroscience,Medicine
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