Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York; Department of Biological Sciences, Fordham University, Bronx, New York.
Biol Psychiatry. 2024 Nov 15;96(10):804-814. doi: 10.1016/j.biopsych.2024.05.021. Epub 2024 Jun 5.
MEF2C is strongly linked to various neurodevelopmental disorders including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity disorder. Mice that constitutively lack 1 copy of Mef2c or selectively lack both copies of Mef2c in cortical excitatory neurons display a variety of behavioral phenotypes associated with neurodevelopmental disorders. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic (gamma-aminobutyric acidergic) inhibitory neurons, but its function in those cell types remains largely unknown.
Using conditional deletions of the Mef2c gene in mice, we investigated the role of MEF2C in parvalbumin-expressing interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at 2 developmental time points. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic INs impacts their survival and maturation and alters brain function and behavior.
Loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic INs led to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior.
MEF2C expression is critical for the development of cortical GABAergic INs, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic INs, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.
MEF2C 与多种神经发育障碍密切相关，包括自闭症、智力障碍、精神分裂症和注意缺陷多动障碍。组成型缺乏 1 个 Mef2c 拷贝或选择性地在皮质兴奋性神经元中缺乏 2 个 Mef2c 拷贝的小鼠显示出与神经发育障碍相关的各种行为表型。MEF2C 蛋白是一种转录因子，对于细胞发育和兴奋性神经元的突触调节是必需的。MEF2C 也在皮质 GABA 能（γ-氨基丁酸能）抑制性神经元的亚群中表达，但它在这些细胞类型中的功能在很大程度上仍然未知。
我们使用小鼠中 Mef2c 基因的条件缺失，研究了 MEF2C 在表达 parvalbumin 的中间神经元（PV-INs）中的作用，PV-INs 是皮质 GABA 能细胞的最大亚群，在 2 个发育时间点进行研究。我们进行了切片电生理学、体内记录和行为测定，以测试 GABA 能 INs 中 MEF2C 的胚胎期和晚期缺失如何影响它们的存活和成熟，并改变大脑功能和行为。
胚胎期而非晚期丢失 MEF2C 从 PV-INs 中丢失导致 PV-IN 数量减少，并且 PV-IN 无法在分子和突触上成熟。与这些缺陷相关的是，GABA 能 INs 中早期的 MEF2C 缺失导致皮质网络活动异常、过度活跃和刻板行为以及认知和社交行为受损。
MEF2C 的表达对于皮质 GABA 能 INs 的发育至关重要，特别是对于 PV-INs。MEF2C 功能的胚胎缺失介导 GABA 能 INs 的功能障碍，导致皮质活动和与神经发育障碍相关的行为表型的体内模式改变。
