Research ArticleDepression

Reversal of Depressed Behaviors in Mice by p11 Gene Therapy in the Nucleus Accumbens

Science Translational Medicine  20 Oct 2010:
Vol. 2, Issue 54, pp. 54ra76
DOI: 10.1126/scitranslmed.3001079

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Dialing Down Depression

Despite much progress in the study and treatment of depression, the mechanisms underlying this debilitating disease are still unclear. Altered activity of several major neurotransmitters in the brain including serotonin is involved, but pinpointing the parts of the brain affected in depression has proved challenging. Alexander and colleagues now implicate a brain region called the nucleus accumbens and a protein called p11 expressed in this region as important mediators of depression in humans and mice.

The authors were alerted to the potential importance of p11 in depression because mice that lack this protein show depressive-like behavior. This protein is involved in the activation of two receptors for serotonin, 5-HT1B and 5-HT4. Alexander et al. decided to down-regulate expression of p11 specifically in the nucleus accumbens by injecting a viral vector containing a small interfering RNA against p11 directly into this brain region in healthy mice. They then tested the treated mice to see if they exhibited depressive-like behaviors in response to two stress tests (suspension by the tail and swimming in a water tank). In both tests, treated mice showed greater immobility compared with control animals, a sign of depressive-like behavior. To show that these depressive symptoms were indeed caused by loss of p11 in the nucleus accumbens, the investigators overexpressed p11 in the nucleus accumbens of mice that completely lacked this protein. They demonstrated restoration of normal immobility times on the two stress tests and an increased desire to sip sucrose solution (a treat that rodents normally enjoy but depressed animals do not). They also showed increased activity of 5-HT1B serotonin receptors expressed by striatal neurons in the nucleus accumbens of mice overexpressing p11. But do these results have any relevance to depression in humans? Alexander and colleagues tackled this question by comparing postmortem nucleus accumbens brain tissue from individuals with and without depression at the time of death. They discovered that expression of p11 was much lower in the nucleus accumbens of depressed individuals compared with healthy persons. These new findings pinpoint the nucleus accumbens and the p11 protein as important mediators of depression and provide new therapeutic targets for drug development.


  • Citation: B. Alexander, J. Warner-Schmidt, T. M. Eriksson, C. Tamminga, M. Arango-Llievano, S. Ghose, M. Vernov, M. Stavarche, S. Musatov, M. Flajolet, P. Svenningsson, P. Greengard, M. G. Kaplitt, Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci. Transl. Med. 2, 54ra76 (2010).