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MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants

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.

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Figure 1: Local lentiviral regulation of MeCP2 in the NAc alters AMPH-induced behaviors.
Figure 2: Mecp2308/y MUT mice show altered AMPH-induced behaviors.
Figure 3: Mecp2308/y MUT mice show altered GABAergic synaptic densities in the NAc.
Figure 4: Chronic treatment with AMPH fails to increase dendritic spine density in Mecp2308/y MUT mice.
Figure 5: Mecp2308/y MUT mice show altered induction of Fos/Jun family IEGs.
Figure 6: Psychostimulants induce phospho-MeCP2 in the NAc.
Figure 7: AMPH selectively induces phospho-MeCP2 in fast-spiking GABAergic interneurons in the NAc.
Figure 8: Increases in phospho-MeCP2 correlate with behavioral sensitization after repeated AMPH administration.

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Acknowledgements

We are deeply grateful to M.E. Greenberg (Harvard Medical School), Z. Zhou and S. Cohen for sharing unpublished data and reagents. We thank N. Calakos (Duke University Medical Center) and F. Polleux (University of North Carolina, Chapel Hill) for providing transgenic mice; K. Vaishnav, J. Zhou, L. Du, M. Fukui, M. Cools, N. Negbenebor, P. Pattabiraman, W.-H. Qian, R. Chereau and M. Presby for technical assistance; and D. Fitzpatrick, G. Feng, J.O. McNamara, A. Brunet and M. Caron for critical reading of the manuscript. Support for this work was provided by National Institute of Drug Abuse grants R01-DA022202 (A.E.W.) and F32-DA025447 (J.V.D.); grant 1-FY07-482 from the March of Dimes Foundation (A.E.W.); along with the Duke University postdoctoral training program in Fundamental and Translational Neuroscience and the predoctoral Pharmacological Sciences Training Program.

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J.V.D. conducted the behavioral and biochemical experiments, performed the stereotactic surgery, ran statistical analyses and wrote the paper. R.M.R. assisted with design and execution of the behavioral experiments and oversaw the statistical analyses. A.N.H. assisted with the behavioral and biochemical experiments and performed the sucrose preference test. I.-H.K. did the Golgi staining. W.C.W. helped to design the study, supervised all behavioral experiments and wrote the paper. A.E.W. designed the study, supervised the project and wrote the paper.

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Correspondence to Anne E West.

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Deng, J., Rodriguiz, R., Hutchinson, A. et al. MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants. Nat Neurosci 13, 1128–1136 (2010). https://doi.org/10.1038/nn.2614

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