Abstract
MeCP2 is a methyl DNA-binding transcriptional regulator that contributes to the development and function of CNS synapses; however, the requirement for MeCP2 in stimulus-regulated behavioral plasticity is not fully understood. Here we show that acute viral manipulation of MeCP2 expression in the nucleus accumbens (NAc) bidirectionally modulates amphetamine (AMPH)-induced conditioned place preference. Mecp2 hypomorphic mutant mice have more NAc GABAergic synapses and show deficient AMPH-induced structural plasticity of NAc dendritic spines. Furthermore, these mice show deficient plasticity of striatal immediate early gene inducibility after repeated AMPH administration. Notably, psychostimulants induce phosphorylation of MeCP2 at Ser421, a site that regulates MeCP2's function as a repressor. Phosphorylation is selectively induced in GABAergic interneurons of the NAc, and its extent strongly predicts the degree of behavioral sensitization. These data reveal new roles for MeCP2 both in mesolimbocortical circuit development and in the regulation of psychostimulant-induced behaviors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amphetamine / pharmacology*
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Animals
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Central Nervous System Stimulants / pharmacology*
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Conditioning, Classical / drug effects
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Conditioning, Classical / physiology
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Corpus Striatum / drug effects
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Corpus Striatum / physiology
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Dendritic Spines / drug effects
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Dendritic Spines / physiology
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Drinking Behavior / drug effects
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Drinking Behavior / physiology
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Genes, Immediate-Early / drug effects
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Interneurons / drug effects
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Interneurons / physiology
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Male
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Methyl-CpG-Binding Protein 2 / genetics
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Methyl-CpG-Binding Protein 2 / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Motor Activity / drug effects
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Motor Activity / physiology
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology
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Nucleus Accumbens / drug effects*
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Nucleus Accumbens / physiology*
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Phosphorylation / drug effects
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Synapses / drug effects
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Synapses / physiology
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gamma-Aminobutyric Acid / metabolism
Substances
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Central Nervous System Stimulants
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Mecp2 protein, mouse
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Methyl-CpG-Binding Protein 2
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gamma-Aminobutyric Acid
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Amphetamine