Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, 92121, USA.
Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Nat Commun. 2017 Nov 14;8(1):1488. doi: 10.1038/s41467-017-01563-8.
Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c (Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.
转录因子 MEF2C 调节与自闭症谱系障碍 (ASD) 相关的多个基因，人类 MEF2C 杂合不足导致 ASD、智力障碍和癫痫。然而，MEF2C 杂合不足综合征的分子机制仍知之甚少。在这里，我们报告 Mef2c（Mef2c-het）小鼠表现出类似于人类患者的行为缺陷。对这些小鼠大脑的基因表达分析显示，与神经发生、突触形成和神经元细胞死亡相关的基因发生变化。因此，Mef2c-het 小鼠表现出神经发生减少、神经元凋亡增强以及兴奋性与抑制性 (E/I) 神经递质传递比例增加。重要的是，神经行为缺陷、E/I 失衡和组织学损伤均通过 NitroSynapsin 治疗得到改善，NitroSynapsin 是一种新型双重作用化合物，与 FDA 批准的药物美金刚有关，是 NMDA 型谷氨酸受体的非竞争性/快速脱靶拮抗剂。这些结果表明，MEF2C 杂合不足导致大脑发育异常、E/I 失衡和神经行为功能障碍，而药物干预可能减轻这些症状。
