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MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212

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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Figure 1: Increased striatal MeCP2 expression in extended access rats.
Figure 2: Dissociable effects of MeCP2 knockdown on cocaine intake.
Figure 3: MeCP2 blunts the effects of cocaine on microRNA-212 expression.
Figure 4: MicroRNA-212 represses MeCP2.
Figure 5: MeCP2–miRNA-212 interplay controls striatal BDNF expression.
Figure 6: Enhanced BDNF expression triggers compulsive cocaine intake.
Figure 7: Disruption of endogenous BDNF transmission decreases cocaine intake.

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References

  1. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Van Esch, H. et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 77, 442–453 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cassel, S. et al. Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain. Mol. Pharmacol. 70, 487–492 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Russo, S.J., Mazei-Robison, M.S., Ables, J.L. & Nestler, E.J. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology 56 (suppl. 1): 73–82 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Nelson, E.D., Kavalali, E.T. & Monteggia, L.M. MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr. Biol. 16, 710–716 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Everitt, B.J. & Robbins, T.W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8, 1481–1489 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Temudo, T. et al. Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type. Mov. Disord. 23, 1384–1390 (2008).

    Article  PubMed  Google Scholar 

  9. Dunn, H.G. Neurons and neuronal systems involved in the pathophysiologies of Rett syndrome. Brain Dev. 23 (suppl. 1): S99–S100 (2001).

    Article  PubMed  Google Scholar 

  10. Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Hollander, J.A. et al. Striatal microRNA controls cocaine intake through CREB signaling. Nature 466, 197–202 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wada, R., Akiyama, Y., Hashimoto, Y., Fukamachi, H. & Yuasa, Y. miR-212 is downregulated and suppresses methyl-CpG-binding protein MeCP2 in human gastric cancer. Int. J. Cancer 127, 1106–1114 (2009).

    Article  Google Scholar 

  13. Klein, M.E. et al. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat. Neurosci. 10, 1513–1514 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Vo, N. et al. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc. Natl. Acad. Sci. USA 102, 16426–16431 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yasui, D.H. et al. Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc. Natl. Acad. Sci. USA 104, 19416–19421 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chang, Q., Khare, G., Dani, V., Nelson, S. & Jaenisch, R. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49, 341–348 (2006).

    CAS  PubMed  Google Scholar 

  17. Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Abuhatzira, L., Makedonski, K., Kaufman, Y., Razin, A. & Shemer, R. MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production. Epigenetics 2, 214–222 (2007).

    Article  PubMed  Google Scholar 

  19. Larimore, J.L. et al. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol. Dis. 34, 199–211 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kondo, M. et al. Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome–Mecp2 gene dosage effects and BDNF expression. Eur. J. Neurosci. 27, 3342–3350 (2008).

    Article  PubMed  Google Scholar 

  21. Horger, B.A. et al. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J. Neurosci. 19, 4110–4122 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Graham, D.L. et al. Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat. Neurosci. 10, 1029–1037 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Graham, D.L. et al. Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward. Biol. Psychiatry 65, 696–701 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Lu, L., Dempsey, J., Liu, S.Y., Bossert, J.M. & Shaham, Y. A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J. Neurosci. 24, 1604–1611 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Grimm, J.W. et al. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J. Neurosci. 23, 742–747 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu, L. et al. Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat. Neurosci. 8, 212–219 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Berglind, W.J. et al. A BDNF infusion into the medial prefrontal cortex suppresses cocaine seeking in rats. Eur. J. Neurosci. 26, 757–766 (2007).

    Article  PubMed  Google Scholar 

  28. Jeanblanc, J. et al. Endogenous BDNF in the dorsolateral striatum gates alcohol drinking. J. Neurosci. 29, 13494–13502 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ahmed, S.H. & Koob, G.F. Transition from moderate to excessive drug intake: change in hedonic set point. Science 282, 298–300 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Piazza, P.V., Deroche-Gamonent, V., Rouge-Pont, F. & Le Moal, M. Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J. Neurosci. 20, 4226–4232 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pelka, G.J., Watson, C.M., Christodoulou, J. & Tam, P.P. Distinct expression profiles of Mecp2 transcripts with different lengths of 3′UTR in the brain and visceral organs during mouse development. Genomics 85, 441–452 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. An, J.J. et al. Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134, 175–187 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Oo, T.F. et al. Brain-derived neurotrophic factor regulates early postnatal developmental cell death of dopamine neurons of the substantia nigra in vivo. Mol. Cell. Neurosci. 41, 440–447 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gemelli, T. et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol. Psychiatry 59, 468–476 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Jin, J. et al. RNAi-induced down-regulation of Mecp2 expression in the rat brain. Int. J. Dev. Neurosci. 26, 457–465 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Chao, H.-T. et al. Loss of MeCP2 in forebrain GABAergic neurons results in impaired motor coordination. in Society for Neuroscience Meeting 310.315 (Washington, D.C., 2008).

  37. Belin, D. & Everitt, B.J. Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 57, 432–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Meehan, R.R., Lewis, J.D. & Bird, A.P. Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res. 20, 5085–5092 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hall, F.S., Drgonova, J., Goeb, M. & Uhl, G.R. Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice. Neuropsychopharmacology 28, 1485–1490 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Schoenbaum, G., Stalnaker, T.A. & Shaham, Y. A role for BDNF in cocaine reward and relapse. Nat. Neurosci. 10, 935–936 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Logrip, M.L., Janak, P.H. & Ron, D. Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake. FASEB J. 22, 2393–2404 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Hasbi, A. et al. Calcium signaling cascade links dopamine D1–D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc. Natl. Acad. Sci. USA 106, 21377–21382 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Choi, K.H., Whisler, K., Graham, D.L. & Self, D.W. Antisense-induced reduction in nucleus accumbens cyclic AMP response element binding protein attenuates cocaine reinforcement. Neuroscience 137, 373–383 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Carlezon, W.A.J. et al. Regulation of cocaine reward by CREB. Science 282, 2272–2275 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Dinieri, J.A. et al. Altered sensitivity to rewarding and aversive drugs in mice with inducible disruption of cAMP response element-binding protein function within the nucleus accumbens. J. Neurosci. 29, 1855–1859 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fasano, S., Pittenger, C. & Brambilla, R. Inhibition of CREB activity in the dorsal portion of the striatum potentiates behavioral responses to drugs of abuse. Front. Behav. Neurosci. 3, 29 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Walters, C.L. & Blendy, J.A. Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. J. Neurosci. 21, 9438–9444 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Huang, Y.H. et al. CREB modulates the functional output of nucleus accumbens neurons: a critical role of N-methyl-D-aspartate glutamate receptor (NMDAR) receptors. J. Biol. Chem. 283, 2751–2760 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Wallace, D.L. et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat. Neurosci. 12, 200–209 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dong, Y. et al. CREB modulates excitability of nucleus accumbens neurons. Nat. Neurosci. 9, 475–477 (2006).

    Article  CAS  PubMed  Google Scholar 

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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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Correspondence to Paul J Kenny.

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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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