Threonine 149 phosphorylation enhances ΔFosB transcriptional activity to control psychomotor responses to cocaine

Hannah M. Cates, Mackenzie Thibault, Madeline Pfau, Elizabeth Heller, Andrew Eagle, Paula Gajewski, Rosemary Bagot, Christopher Colangelo, Thomas Abbott, Gabby Rudenko, Rachael Neve, Eric J. Nestler, Alfred J. Robison

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Stable changes in neuronal gene expression have been studied as mediators of addicted states. Of particular interest is the transcription factor ΔFosB, a truncated and stable FosB gene product whose expression in nucleus accumbens (NAc), a key reward region, is induced by chronic exposure to virtually all drugs of abuse and regulates their psychomotor and rewarding effects. Phosphorylation at Ser27 contributes to ΔFosB's stability and accumulation following repeated exposure to drugs, and our recent work demonstrates that the protein kinase CaMKIIα phosphorylates ΔFosB at Ser27 and regulates its stability in vivo. Here, we identify two additional sites on ΔFosB that are phosphorylated in vitro by CaMKIIα, Thr149 and Thr180, and demonstrate their regulation in vivo by chronic cocaine. We show that phosphomimetic mutation of Thr149 (T149D) dramatically increases AP-1 transcriptional activity while alanine mutation does not affect transcriptional activity when compared with wild-type (WT) ΔFosB. Using in vivo viral-mediated gene transfer of ΔFosB-T149D or ΔFosB-T149A in mouse NAc, we determined that overexpression of ΔFosB-T149D in NAc leads to greater locomotor activity in response to an initial low dose of cocaine than does WT ΔFosB, while overexpression of ΔFosB-T149A does not produce the psychomotor sensitization to chronic low-dose cocaine seen after overexpression of WT ΔFosB and abrogates the sensitization seen in control animals at higher cocaine doses. We further demonstrate that mutation of Thr149 does not affect the stability of ΔFosB overexpressed in mouse NAc, suggesting that the behavioral effects of these mutations are driven by their altered transcriptional properties.

Original languageEnglish (US)
Pages (from-to)11461-11469
Number of pages9
JournalJournal of Neuroscience
Volume34
Issue number34
DOIs
StatePublished - Aug 20 2014

Keywords

  • Accumbens
  • CaMKII
  • Cocaine
  • Phosphorylation
  • Transcription
  • δFosB

ASJC Scopus subject areas

  • Neuroscience(all)

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    Cates, H. M., Thibault, M., Pfau, M., Heller, E., Eagle, A., Gajewski, P., Bagot, R., Colangelo, C., Abbott, T., Rudenko, G., Neve, R., Nestler, E. J., & Robison, A. J. (2014). Threonine 149 phosphorylation enhances ΔFosB transcriptional activity to control psychomotor responses to cocaine. Journal of Neuroscience, 34(34), 11461-11469. https://doi.org/10.1523/JNEUROSCI.1611-14.2014