Investigating novel therapeutic targets for the treatment of major depressive disorder

Major depressive disorder (MDD) affects about one in five people worldwide, and currently there are only limited pharmacological treatments available. Ketamine, a non-competitive NMDA receptor (NMDAR) antagonist, has been shown to have rapid-acting antidepressant effects in people with MDD, including those with treatment-resistant depression, but it can have psychotic side-effects It is important to understand the molecular mechanism underlying ketamine’s antidepressant effect so that better therapeutics can be developed. Evidence from in vitro studies suggests that ketamine is a partial channel blocker of NMDARs. However, our recent results using mouse lines containing mutations in the NMDAR cytoplasmic domain (CTD) show that in vivo the rapid ketamine behavioural effect is mediated by the NMDAR CTD, not channel blockade.

We want to investigate the long-lasting antidepressant effect of ketamine in these knock-in mice. With biochemical analysis of their ketamine-treated brains, we want to elucidate underlying molecular pathways and molecular targets among the proteins forming complexes with the NMDAR CTD. We plan to investigate the dose-dependent effect of ketamine (psychotomimetic vs. antidepressant) with a novel synaptic activity reporter (Arc-Venus mouse) combined with NMDAR CTD mutants.

Our goal is to generate solid preliminary data for future funding applications and our findings will help with the development of better therapies for MDD.