Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes

被引:866
作者
Chao, Hsiao-Tuan [1 ,2 ]
Chen, Hongmei [2 ]
Samaco, Rodney C. [2 ]
Xue, Mingshan [1 ]
Chahrour, Maria [2 ]
Yoo, Jong [3 ]
Neul, Jeffrey L. [4 ,5 ]
Gong, Shiaoching [7 ,8 ]
Lu, Hui-Chen [4 ,5 ]
Heintz, Nathaniel [7 ,8 ]
Ekker, Marc [9 ]
Rubenstein, John L. R. [10 ]
Noebels, Jeffrey L. [1 ,2 ,3 ]
Rosenmund, Christian [1 ,2 ]
Zoghbi, Huda Y. [1 ,2 ,3 ,4 ,5 ,6 ]
机构
[1] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
[5] Baylor Coll Med, Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA
[6] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA
[7] Rockefeller Univ, New York, NY 10021 USA
[8] Howard Hughes Med Inst, New York, NY 10021 USA
[9] Univ Ottawa, Dept Biol, Ctr Adv Res Environm Genom, Ottawa, ON K1N 6N5, Canada
[10] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94158 USA
关键词
GLUTAMIC-ACID DECARBOXYLASE; CPG-BINDING PROTEIN-2; MOUSE MODEL; NEURONAL MECP2; YOUNG GIRLS; 67; KDA; MICE; GENE; SCHIZOPHRENIA; MUTATION;
D O I
10.1038/nature09582
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 (c-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.
引用
收藏
页码:263 / 269
页数:7
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