Cocaine Regulates MEF2 to Control Synaptic and Behavioral Plasticity

Suprabha Pulipparacharuvil, William Renthal, Carly F. Hale, Makoto Taniguchi, Guanghua Xiao, Arvind Kumar, Scott J. Russo, Devanjan Sikder, Colleen M. Dewey, Maya M. Davis, Paul Greengard, Angus C. Nairn, Eric J. Nestler, Christopher W. Cowan

Research output: Contribution to journalArticle

183 Scopus citations

Abstract

Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine.

Original languageEnglish (US)
Pages (from-to)621-633
Number of pages13
JournalNeuron
Volume59
Issue number4
DOIs
StatePublished - Aug 28 2008

Keywords

  • MOLNEURO
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

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    Pulipparacharuvil, S., Renthal, W., Hale, C. F., Taniguchi, M., Xiao, G., Kumar, A., Russo, S. J., Sikder, D., Dewey, C. M., Davis, M. M., Greengard, P., Nairn, A. C., Nestler, E. J., & Cowan, C. W. (2008). Cocaine Regulates MEF2 to Control Synaptic and Behavioral Plasticity. Neuron, 59(4), 621-633. https://doi.org/10.1016/j.neuron.2008.06.020