Abstract
The X-linked transcriptional repressor methyl CpG binding protein 2 (MeCP2), known for its role in the neurodevelopmental disorder Rett syndrome, is emerging as an important regulator of neuroplasticity in postmitotic neurons. Cocaine addiction is commonly viewed as a disorder of neuroplasticity, but the potential involvement of MeCP2 has not been explored. Here we identify a key role for MeCP2 in the dorsal striatum in the escalating cocaine intake seen in rats with extended access to the drug, a process that mimics the increasingly uncontrolled cocaine use seen in addicted humans. MeCP2 regulates cocaine intake through homeostatic interactions with microRNA-212 (miR-212) to control the effects of cocaine on striatal brain-derived neurotrophic factor (BDNF) levels. These data suggest that homeostatic interactions between MeCP2 and miR-212 in dorsal striatum may be important in regulating vulnerability to cocaine addiction.
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Acknowledgements
We thank B. Xu from Georgetown University for the BDNF 3′-UTR reporter construct. This work was supported by a grant from the US National Institute on Drug Abuse to P.J.K. (DA025983); Ruth L. Kirschstein National Research Service Awards to H.-I.I. and J.A.H.; and a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award to H.-I.I. This is manuscript number 20438 from The Scripps Research Institute.
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H.-I.I., J.A.H. and P.B. conducted all experiments. H.-I.I. and P.J.K. designed the experiments and wrote the manuscript.
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Im, HI., Hollander, J., Bali, P. et al. MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nat Neurosci 13, 1120–1127 (2010). https://doi.org/10.1038/nn.2615
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DOI: https://doi.org/10.1038/nn.2615
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