A synaptic substrate for ketamine-mediated amelioration of stress-induced anhedonia

SUMMARY Depression is a leading cause of morbidity and mortality worldwide and it is projected to become the second leading cause of disability by 2030. Despite these results indicate the urgent need to address depression as a public-health priority to reduce disease burden and disability, current pharmacotherapies for depression require prolonged administration (weeks if not months) for clinical improvement and they are often associated with high non-response rate. In contrast, recent clinical evidence has shown that a single sub-anesthetic dose of ketamine induces a robust and rapid (within matter of hours) antidepressant effect in 70% of treatment-resistant patients. Notably, ketamine is the first rapid-acting antidepressant with efficacy for treatment-resistant symptoms of major depression disorder such as anhedonia. Anhedonia, defined as diminished pleasure from, or interest in, previously rewarding activities is commonly precipitated by exposure to chronic stress and it is well suited to study in laboratory animals. Whereas ketamine’s primary molecular target is under debate, there is broad consensus in the literature that activation of the AMPAR as well as induction of synaptogenesis driven by de novo protein synthesis-dependent mechanisms are required for ketamine’s ability to ameliorate stress-induced anhedonia. Nevertheless, major technical barriers have hindered a circuit and synaptic-level dissection of such mechanisms. Therefore, understanding the detailed circuit and synaptic mechanisms and establishing a causal link between ketamine- evoked AMPAR-mediated synaptic plasticity and specific behavioral outcomes is crucial for designing novel and safer therapeutic targets. Here, we will tackle this question by using electrophysiology, optogenetics and recently developed technologies that offer the unprecedented opportunity to block AMPAR as well as de novo protein synthesis within genetically specified cells. Accordingly, the following hypotheses will be tested: (i) increased AMPAR-mediated synaptic transmission on D1-MSNs mediates the anti-anhedonic effects of ketamine, (ii) mPFC->NAc input is necessary for ketamine-mediated amelioration of stress-induced anhedonia, and (iii) ketamine-induced de novo protein synthesis-dependent plasticity in D1-MSNs drives ketamine-mediated amelioration of stress-induced anhedonia. Altogether, results from these studies will increase our understanding of the mechanisms of action of ketamine and might lead to new potential targets to treat stress-induced anhedonia.