title: Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory.
abstract: DNA methylation-dependent epigenetic mechanisms underlie the development and function of the mammalian brain. MeCP2 is highly expressed in neurons and functions as a molecular linker between DNA methylation, chromatin remodeling and transcription regulation. Previous in vitro studies have shown that neuronal activity-induced phosphorylation (NAIP) of methyl CpG-binding protein 2 (MeCP2) precedes its release from the Bdnf promoter and the ensuing Bdnf transcription. However, the in vivo function of this phosphorylation event remains elusive. We generated knock-in mice that lack NAIP of MeCP2 and found that they performed better in hippocampus-dependent memory tests, presented enhanced long-term potentiation at two synapses in the hippocampus and showed increased excitatory synaptogenesis. At the molecular level, the phospho-mutant MeCP2 protein bound more tightly to several MeCP2 target gene promoters and altered the expression of these genes. Our results suggest that NAIP of MeCP2 is required for modulating dynamic functions of the adult mouse brain.
authors.affiliation: Genetics Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Hongda
authors.initials: H
authors.lastname: Li
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Zhong
authors.forename: Kevin Fongching
authors.initials: KF
authors.lastname: Chau
authors.forename: Emily Cunningham
authors.initials: EC
authors.lastname: Williams
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
mesh_terms: D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001703:Biophysics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005239:Fear / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000502:physiology*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011189:Potassium Chloride / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D013028:Space Perception / Q000502:physiology*; D013550:Swimming / Q000523:psychology; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C497393:Mecp2 protein, mouse; D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D013779:Tetrodotoxin; D012694:Serine; D011189:Potassium Chloride; D051528:Guanylate Kinases; D010751:Phosphopyruvate Hydratase