Journal Article

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

Zoghbi, Huda Y., Ekker, Marc, Rosenmund, Christian, Heintz, Nathaniel, Chao, Hsiao-Tuan, Gong, Shiaoching, Xue, Mingshan, Chahrour, Maria, Yoo, Jong, Lu, Hui-Chen, Rubenstein, John L. R., Noebels, Jeffrey L., Samaco, Rodney C., Neul, Jeffrey L., Chen, Hongmei

2010

Overview

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. The GABAergic system in Rett syndrome Rett syndrome, a neurodevelopmental disorder with autistic features, is caused by mutations in the methyl-CpG-binding protein 2 gene ( MECP2 ). A number of mouse models with full and cell-type specific deletions of Mecp2 have been generated, but show only a subset of the signs of Rett syndrome. Now Huda Zoghbi and colleagues report that mice with selective deletion of MeCP2 in GABAergic neurons show not only impaired GABAergic function, but capitulate many of the key features of Rett syndrome. The finding that disturbance of inhibitory neurons causes a variety of neuropsychiatric phenotypes suggests that the GABAergic system may be a promising target for therapeutic intervention. Mutations in the methyl-CpG-binding protein 2 (MeCP2) gene cause Rett syndrome, a neurodevelopmental disorder with features of autism. Multiple mouse models of MeCP2 have been generated, but show only a subset of the symptoms of Rett syndrome. These authors find that mice with selective deletion of MeCP2 in GABA-mediated neurons show not only impaired GABA-mediated function, but capitulate multiple key features of Rett, further suggesting a role of inhibitory function in neuropsychiatric disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/548 / 631/601/18 / 692/699/375/366 / Adult and adolescent clinical studies / Animals / Anxiety / Autism / Autistic Disorder - complications / Autistic Disorder - genetics / Autistic Disorder - pathology / Autistic Disorder - physiopathology / Behavior / Biological and medical sciences / Bipolar disorder / Brain - cytology / Care and treatment / Cognition disorders / Compulsive Behavior - complications / Compulsive Behavior - genetics / Compulsive Behavior - physiopathology / Diagnosis / Disease Models, Animal / Electroencephalography / Fundamental and applied biological sciences. Psychology / GABA / gamma-Aminobutyric Acid - metabolism / Gene expression / Genetic aspects / Genotype / Glutamate Decarboxylase - metabolism / Health aspects / Hippocampus - pathology / Hippocampus - physiopathology / Homeodomain Proteins - genetics / Humanities and Social Sciences / Inhibitory Postsynaptic Potentials / Long-Term Potentiation / Male / Medical sciences / Mental disorders / Methyl-CpG-Binding Protein 2 - deficiency / Methyl-CpG-Binding Protein 2 - genetics / Methyl-CpG-Binding Protein 2 - metabolism / Mice / Mice, Transgenic / multidisciplinary / Neural Inhibition / Neuronal Plasticity / Neurons / Neurons - metabolism / Phenotype / Presynaptic Terminals - metabolism / Psychology. Psychoanalysis. Psychiatry / Psychomotor Disorders - complications / Psychomotor Disorders - genetics / Psychomotor Disorders - physiopathology / Psychopathology. Psychiatry / Psychoses / Reflex, Startle - genetics / Respiration / Rett syndrome / Rett Syndrome - complications / Rett Syndrome - genetics / Rett Syndrome - pathology / Rett Syndrome - physiopathology / Rodents / Schizophrenia / Science / Science (multidisciplinary) / Seizures (Medicine) / Self-Injurious Behavior - complications / Self-Injurious Behavior - genetics / Self-Injurious Behavior - physiopathology / Signal Transduction / Social interaction / Stereotypic Movement Disorder - complications / Stereotypic Movement Disorder - genetics / Stereotypic Movement Disorder - pathology / Stereotypic Movement Disorder - physiopathology / Studies / Survival Rate / Synaptic Transmission / Vertebrates: nervous system and sense organs / Vesicular Inhibitory Amino Acid Transport Proteins - genetics