Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome.
The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2(+/-) mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
Kerstin
K
Ure
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
Hui
H
Lu
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
Wei
W
Wang
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
Aya
A
Ito-Ishida
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Department of Pediatrics, Baylor College of Medicine, Houston, United States.
Zhenyu
Z
Wu
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
Ling-Jie
LJ
He
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
Yehezkel
Y
Sztainberg
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Cain Foundation Laboratories, Baylor College of Medicine, Houston, United States.
Wu
W
Chen
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Department of Pediatrics, Baylor College of Medicine, Houston, United States.
Jianrong
J
Tang
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.|Department of Neuroscience, Baylor College of Medicine, Houston, United States.
Huda Y
0000-0002-0700-3349
HY
Zoghbi
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology*; D015870:Gene Expression; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology*
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2
GABAergic neurons; Rett syndrome; inhibition; mouse; neuroscience