Antidepressant ketamine and its metabolite hydroxynorketamine converge on the regulation of neurotransmitter release

Major depressive disorder (MDD) is a devitalizing psychiatric condition with a lifetime prevalence of 17%. Alterations in glutamatergic transmission and plasticity have been closely associated with MDD. Ketamine is an activity-dependent blocker of NMDA receptors (NMDAR) which, at low subanesthetic doses show rapid and sustained antidepressant effect in treatment resistant patients. Changes in neuronal plasticity and synaptic transmission have been associated with antidepressant effects of ketamine. However, psychotomimetic effects and abuse potential of ketamine cannot be ignored and thus, its off-label use remains limited. A fairly recent study suggested that not ketamine but its metabolite hydroxynorketamine (HNK), which does not act via NMDAR, mediates the rapid antidepressant action. The molecular mechanisms of ketamine and HNK induced antidepressant effect remain enigmatic. In this study, we set up to monitor the effects of ketamine and HNK in cultured cortical neurons using live-cell imaging and electrophysiology, to investigate the convergent and divergent effects of these drugs on neurotransmission, signaling and gene expression, at the level of individual cells and synapses. Our results indicate that low doses of ketamine and HNK show convergent effect on neurotransmitter release and thus modulate neurotransmission rapidly and persistently. Hereon, we provide a mechanistic understanding of cellular signaling mediating the antidepressant effect of ketamine and its metabolite HNK