]Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature. 2010 Nov 11;468(7321):263-9. doi: 10.1038/nature09582.
Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (γ-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.
X 连锁的 MECP2 基因突变，该基因编码转录调控因子甲基化-CpG 结合蛋白 2（MeCP2），可导致雷特综合征和几种神经发育障碍，包括认知障碍、自闭症、青少年起病的精神分裂症和伴早期致死性的脑病。雷特综合征的特征是早期发育明显正常，随后出现退行性变、运动异常、癫痫发作和自闭症特征，特别是刻板行为。介导这些特征的机制尚未完全理解。在这里，我们展示了从 GABA（γ-氨基丁酸）释放神经元中缺乏 Mecp2 的小鼠重现了许多雷特综合征和自闭症特征，包括重复行为。从前脑 GABA 能神经元中缺失一部分 MeCP2 也重现了许多雷特综合征的特征。缺乏 MeCP2 的 GABA 能神经元显示出抑制性量子大小减小，与谷氨酸脱羧酶 1（Gad1）和谷氨酸脱羧酶 2（Gad2）水平以及 GABA 免疫反应性的突触前减少一致。这些数据表明，MeCP2 对于 GABA 释放神经元的正常功能至关重要，而 GABA 能神经元的细微功能障碍导致许多神经精神表型。
