Science 6 January 2006:Vol

Depression is a mood continuum, ranging from normal but temporary "bad days" to a completely disabling clinical condition characterized by overwhelming despair that lasts for weeks or months. A popular theory is that a breakdown in signaling by the brain neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is critically involved in the symptoms of clinical depression, but the nature of this defect has proved elusive. The study by Svenningsson et al. on page 77 of this issue (1) identifies a powerful interaction between a brain protein called p11 and a serotonin receptor (5-HT1B subtype) that has been previously associated with mood regulation. Moreover, in a clever set of experiments using human brain and sophisticated animal models, the authors show that a deficit of p11 is linked to depression, whereas an increase in p11 is linked to the relief of depression. Overall, this finding represents compelling evidence that p11 has a pivotal role in both the cause of depression and perhaps its successful treatment.