Grant: Operating Grant

Major depression is the most prevalent mental illness, and 1/6 people are diagnosed as depressed in their lifetime. Multiple lines of evidence implicate reduced activity of the serotonin system in major depression. However, current antidepressants produce remission in less than 1/3 of patients. Hence there is a need for a better understanding of the serotonin system in depression, and we have hypothesized that a specific genetic change (polymorphism) in the serotonin system may lead to depression. This proposal addresses how that change can cause depression using a new animal model. Our CIHR-funded research has identified a new functional genetic marker for major depression, suicide and reduced response to antidepressants, the C(-1019)G 5-HT1A polymorphism. This polymorphism prevents the action of genetic regulators and is expected to increase levels of serotonin-1A receptor, which inhibits serotonin activity in the brain, a key hallmark of depression. We will address the hypothesis that genetic regulators that target the polymorphism will play critical roles in regulation of the serotonin-1A receptor in the brain, with important consequences for serotonin activity and behavior. We will use mouse models lacking key genetic regulators of this receptor and examine the consequences for levels of receptor, serotonin activity and depression behaviours in the mice. Our initial studies show changes in the levels of serotonin-1A receptors as predicted from our cell models, and we will now examine the mice for depression or anxiety behaviours, and for response to antidepressant treatments. We will generate important new animal models of depression, which will identify key roles for specific genetic regulators in depression and response to antidepressant treatments. This new information will provide the basis for new strategies to treat antidepressant-resistant depression by targeting these novel transcriptional regulators.