title: Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures.
abstract: Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability.
authors: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors: Wen
authors: W
authors: Zhang
authors: Matthew
authors: M
authors: Peterson
authors: Barbara
authors: B
authors: Beyer
authors: Wayne N
authors: WN
authors: Frankel
authors: Zhong-wei
authors: ZW
authors: Zhang
mesh_terms: D000818:Animals; D004569:Electroencephalography; D007150:Immunohistochemistry; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D016548:Prosencephalon / Q000378:metabolism* / Q000503:physiopathology; D015518:Rett Syndrome / Q000378:metabolism / Q000503:physiopathology; D012640:Seizures / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D005680:gamma-Aminobutyric Acid
keywords: GABA; Rett syndrome; hyperexcitation; neocortex; pyramidal neuron; seizure