Project 462065

Depression is a stress-related mood disorder that affects 300 million people worldwide. Considering that up to 30% of depressed patients are resistant to current treatments, the development of more effective antidepressants is warranted. N-methyl-D-aspartate receptor (NMDAR) could be an imperative therapeutic target for treating depression. Not only the expression of depression symptoms can be modeled by manipulating NMDAR function in animal studies, NMDAR antagonist such as ketamine has been used as a fast-acting antidepressant. In this project grant, we propose that a subpopulation of NMDARs that express outside synapses are crucial for enhancing our resistance to stress from developing depression symptoms. These so called extrasynaptic NMDARs could be specifically targeted by newly developed drugs in my laboratory for examining their roles in the vulnerability to stress and depression. In this project grant, we will use several animal models of chronic stress to test a hypothesis that enhancing extrasynaptic NMDAR function in a brain region called the hippocampus could increase our resilience to stress and ameliorate depression-related symptoms. We will examine molecular mechanisms that underlie pro-resilience effects of extrasynaptic NMDARs. The contribution of extrasynaptic NMDAR to the enhanced stress sensitivity in females will also be examined. Finally, we will focus on the effects of extrasynaptic NMDAR-targeting drugs on cognitive symptoms that are related to depression. Findings from this study could lead to the development of next generation of antidepressants for treating cognitive symptoms of depression. These antidepressants could also be used to reduce the vulnerability to depression in women.