title: MeCP2 phosphorylation limits psychostimulant-induced behavioral and neuronal plasticity.
abstract: The methyl-DNA binding protein MeCP2 is emerging as an important regulator of drug reinforcement processes. Psychostimulants induce phosphorylation of MeCP2 at Ser421; however, the functional significance of this posttranslational modification for addictive-like behaviors was unknown. Here we show that MeCP2 Ser421Ala knock-in mice display both a reduced threshold for the induction of locomotor sensitization by investigator-administered amphetamine and enhanced behavioral sensitivity to the reinforcing properties of self-administered cocaine. These behavioral differences were accompanied in the knock-in mice by changes in medium spiny neuron intrinsic excitability and nucleus accumbens gene expression typically observed in association with repeated exposure to these drugs. These data show that phosphorylation of MeCP2 at Ser421 functions to limit the circuit plasticities in the nucleus accumbens that underlie addictive-like behaviors.
authors.affiliation: Department of Neurobiology, Center for Translational Neuroscience, Department of Neurology, Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02132, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida 32610.
authors.forename: Jie V
authors.initials: JV
authors.lastname: Deng
authors.forename: Yehong
authors.initials: Y
authors.lastname: Wan
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wang
authors.forename: Sonia
authors.initials: S
authors.lastname: Cohen
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
authors.forename: Nicole
authors.initials: N
authors.lastname: Calakos
authors.forename: Anne E
authors.initials: AE
authors.lastname: West
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage; D003342:Corpus Striatum / Q000166:cytology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D005106:Exploratory Behavior / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics*; D009474:Neurons / Q000187:drug effects*; D010766:Phosphorylation / Q000502:physiology; D012646:Self Administration
chemical_list: D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D000661:Amphetamine; D003042:Cocaine
keywords: GABAergic interneurons; MeCP2; cocaine self-administration; intrinsic excitability; nucleus accumbens; psychostimulants