Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.
Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.
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编码转录调节因子甲基-CpG结合蛋白2（MeCP 2）的X连锁MECP 2中的突变引起Rett综合征（RTT）和几种神经发育障碍，包括认知障碍、自闭症、青少年发作的精神分裂症和具有早期致死性的脑病。RTT的特征是早期发育明显正常，随后出现退化、运动异常、癫痫发作和自闭症特征，尤其是刻板行为。调节这些显著特征的机制知之甚少。在这里，我们发现，缺乏γ-氨基丁酸（GABA）能神经元Mecp 2的小鼠重现了许多RTT和自闭症特征，包括重复行为。前脑GABA能神经元亚群中MeCP 2的缺失也概括了RTT的许多特征。MeCP 2缺陷型GABA能神经元显示抑制量子大小减少，这与谷氨酸脱羧酶-1和-2水平和GABA免疫反应性的突触前减少一致。这些数据表明，MeCP 2是正常的GABA能神经元功能的关键，GABA能神经元的微妙功能障碍有助于许多神经精神表型。
Mutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is characterized by apparently normal early development followed by regression, motor abnormalities, seizures, and features of autism, especially stereotyped behaviors. The mechanisms mediating these striking features are poorly understood. Here we show that mice lacking Mecp2 from γ-amino-butyric-acid-(GABA)-ergic neurons recapitulate numerous RTT and autistic features, including repetitive behaviors. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of RTT. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size consistent with presynaptic reduction in glutamic acid decarboxylase-1 and -2 levels and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal GABAergic neuronal function and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.
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