Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.
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.
]Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Hsiao-Tuan
HT
Chao
Hongmei
H
Chen
Rodney C
RC
Samaco
Mingshan
M
Xue
Maria
M
Chahrour
Jong
J
Yoo
Jeffrey L
JL
Neul
Shiaoching
S
Gong
Hui-Chen
HC
Lu
Nathaniel
N
Heintz
Marc
M
Ekker
John L R
JL
Rubenstein
Jeffrey L
JL
Noebels
Christian
C
Rosenmund
Huda Y
HY
Zoghbi
D000818:Animals; D001321:Autistic Disorder / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000166:cytology; D003192:Compulsive Behavior / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics; D053444:Inhibitory Postsynaptic Potentials; D017774:Long-Term Potentiation; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D017729:Presynaptic Terminals / Q000378:metabolism; D011596:Psychomotor Disorders / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D013216:Reflex, Startle / Q000235:genetics; D012119:Respiration; D015518:Rett Syndrome / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016728:Self-Injurious Behavior / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction; D019956:Stereotypic Movement Disorder / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D015996:Survival Rate; D009435:Synaptic Transmission; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D018398:Homeodomain Proteins; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2