Trudler Dorit, Ghatak Swagata, Bula Michael, Parker James, Talantova Maria, Luevanos Melissa, Labra Sergio, Grabauskas Titas, Noveral Sarah Moore, Teranaka Mayu, Schahrer Emily, Dolatabadi Nima, Bakker Clare, Lopez Kevin, Sultan Abdullah, Patel Parth, Chan Agnes, Choi Yongwook, Kawaguchi Riki, Stankiewicz Pawel, Garcia-Bassets Ivan, Kozbial Piotr, Rosenfeld Michael G, Nakanishi Nobuki, Geschwind Daniel H, Chan Shing Fai, Lin Wei, Schork Nicholas J, Ambasudhan Rajesh, Lipton Stuart A
Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, USA.
Mol Psychiatry. 2025 Apr;30(4):1479-1496. doi: 10.1038/s41380-024-02761-9. Epub 2024 Sep 30.
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.
MEF2C是神经发育过程中的关键转录因子，其在人类中的功能丧失突变会导致MEF2C单倍体不足综合征（MHS），这是自闭症谱系障碍（ASD）/智力障碍（ID）的一种严重形式。尽管之前有动物研究通过MEF2C杂合性来模拟MHS，但此前尚未对MHS特异性突变进行研究，特别是在人类背景下利用人诱导多能干细胞（hiPSC）所提供的研究条件。在此，我们首次使用患者来源的hiPSC分化的大脑皮质神经元和脑类器官来表征MHS缺陷。出乎意料的是，我们发现神经发生减少伴随着微小（mi）RNA介导的神经胶质生成途径的激活。我们还证明了MHS神经元在网络水平上的过度兴奋性，表现为过多的突触和突触外活动导致兴奋/抑制（E/I）失衡。值得注意的是，主要作用于突触外（e）N-甲基-D-天冬氨酸（NMDA）受体的拮抗剂NitroSynapsin可纠正这种与异常表型相关的异常电活动。在神经发育过程中，MEF2C调节许多与ASD相关的基因网络，这表明治疗MHS缺陷可能也有助于治疗其他形式的ASD。
