A novel role of the WNT-dishevelled-GSK3β signaling cascade in the mouse nucleus accumbens in a social defeat model of depression

Matthew B. Wilkinson, Caroline Dias, Jane Magida, Michelle Mazei-Robison, Marykay Lobo, Pamela Kennedy, David Dietz, Herbert Covington, Scott Russo, Rachael Neve, Subroto Ghose, Carol Tamminga, Eric J. Nestler

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Based on earlier gene expression and chromatin array data, we identified the protein, dishevelled (DVL)-2, as being regulated in the nucleus accumbens (NAc), a key brain reward region, in the mouse social defeat model of depression. Here, we validate these findings by showing that DVL2 mRNA and protein levels are downregulated in NAc of mice susceptible to social defeat stress, effects not seen in resilient mice. OtherDVLisoforms, DVL1 and DVL3, show similar patterns of regulation. Downregulation of DVL was also demonstrated in the NAc of depressed humans examined postmortem. Interestingly, several members of the WNT (Wingless)-DVL signaling cascade, including phospho-GSK3_ (glycogen synthase kinase-3_), also show significant downregulation in the NAc of susceptible, but not resilient, mice, demonstrating concerted regulation of this pathway in the NAc due to social defeat stress. By using viral-mediated gene transfer to overexpress a dominant-negative mutant of DVL in NAc, or by using a pharmacological inhibitor of DVL administered into this brain region, we show that blockade of DVL function renders mice more susceptible to social defeat stress and promotes depression like behavior in other assays. Similar prodepression-like effects were induced upon overexpressing GSK3_ in the NAc, while overexpressing a dominant-negative mutant of GSK3_ promoted resilience to social defeat stress. These findings are consistent with the knowledge that downregulation of DVL and phospho-GSK3_ reflects an increase in GSK3_ activity. These studies reveal a novel role for the DVL-GSK3β signaling pathway, acting within the brain's reward circuitry, in regulating susceptibility to chronic stress.

Original languageEnglish (US)
Pages (from-to)9084-9092
Number of pages9
JournalJournal of Neuroscience
Volume31
Issue number25
DOIs
StatePublished - Jun 22 2011

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'A novel role of the WNT-dishevelled-GSK3β signaling cascade in the mouse nucleus accumbens in a social defeat model of depression'. Together they form a unique fingerprint.

  • Cite this

    Wilkinson, M. B., Dias, C., Magida, J., Mazei-Robison, M., Lobo, M., Kennedy, P., Dietz, D., Covington, H., Russo, S., Neve, R., Ghose, S., Tamminga, C., & Nestler, E. J. (2011). A novel role of the WNT-dishevelled-GSK3β signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. Journal of Neuroscience, 31(25), 9084-9092. https://doi.org/10.1523/JNEUROSCI.0039-11.2011