title: Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model.
abstract: Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice.
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Hui
authors: H
authors: Lu
authors: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Ryan T
authors: RT
authors: Ash
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute,, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Lingjie
authors: L
authors: He
authors: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Sara E
authors: SE
authors: Kee
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Wei
authors: W
authors: Wang
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Dinghui
authors: D
authors: Yu
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Shuang
authors: S
authors: Hao
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Xiangling
authors: X
authors: Meng
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Kerstin
authors: K
authors: Ure
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Aya
authors: A
authors: Ito-Ishida
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Bin
authors: B
authors: Tang
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute,, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Yaling
authors: Y
authors: Sun
authors: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Daoyun
authors: D
authors: Ji
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Jianrong
authors: J
authors: Tang
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Benjamin R
authors: BR
authors: Arenkiel
authors: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Stelios M
authors: SM
authors: Smirnakis
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute,, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hzoghbi@bcm.edu.
authors: Huda Y
authors: HY
authors: Zoghbi
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000503:physiopathology*; D046690:Deep Brain Stimulation; D004195:Disease Models, Animal; D005260:Female; D020712:Fornix, Brain / Q000502:physiology*; D020440:Gene Duplication / Q000235:genetics; D006706:Homeostasis / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009030:Mosaicism; D009154:Mutation / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology; D015518:Rett Syndrome / Q000235:genetics / Q000503:physiopathology*
chemical_list: D051783:Methyl-CpG-Binding Protein 2