Grant: Project Grant

Depression is a debilitating mental disorder affecting over 350 million people globally and is associated with high personal and socioeconomic burden. Efficacy of classical antidepressant medications, including selective serotonin reuptake inhibitors and tricyclic antidepressants is compromised by extended delays to achieve therapeutic efficacy. Sadly, 50% of patients with treatment-resistant depression (TRD) do not obtain remission with traditional antidepressants. One of the most exciting discoveries in neuropharmacology in two decades is that a single intravenous infusion of ketamine has robust, rapid and sustained antidepressant effects in individuals with TRD lasting up to 1-2 weeks. Not surprisingly, this discovery has inspired great interest in identifying the underlying molecular mechanisms. Ketamine blocks the NMDA class of glutamate receptors, consistent with dysfunctions within the glutamatergic system and dysregulation of synaptic plasticity in the pathophysiology of depression. Systematic investigations of ketamine's effects on in vivo synaptic plasticity in animal models of depression, as well as direct contribution of synaptic plasticity changes to ketamine's antidepressant effects, are key to understanding the mechanisms by which ketamine and other candidate drugs achieve their unique effects. Proposed experiments will utilize a genetic model of depression (Wistar-Kyoto WKY rat). In preliminary experiments we observed weakness in synaptic plasticity that was rescued by ketamine. Therefore, we hypothesize that impaired synaptic plasticity in WKY rats causes depression-like deficits in motivation, cognition, and social interaction. Furthermore, we propose that restitution of synaptic plasticity is a crucial mediator of the antidepressant response to ketamine. Novel candidate compounds will be screened using the WKY model of TRD.