Exploring the molecular determinants of behavioral changes induced by ketamine at the nanoscale – CHAIN

The discovery of the antidepressant properties of ketamine has changed our understanding of major depressive disorders and raised high hopes for the development of new fast-acting drugs. Indeed, while classic antidepressants take weeks to act and are often inefficient - with 30% of patients not responding to treatment - administration of a single dose of ketamine evokes rapid and robust antidepressant responses in patients with treatment-resistant depression. Unfortunately, several aspects of the action mode of ketamine remain enigmatic, and its clinical use is strongly limited by severe psychotic-like adverse effects. Thus, a better understanding of the mechanisms underpinning its rapid antidepressant efficacy and psychotomimetic traits is essential to identify new targets for safe therapeutic intervention in major depressive disorder. Used for over fifty years as an anesthetic, ketamine exerts its sedative properties by blocking N-Methyl-D-Aspartate glutamate receptors (NMDAR) - central actors of synaptic plasticity, brain development and cognition - and it has been assumed that its antidepressant and psychotomimetic actions likely also rely on NMDAR inhibition. However, while major efforts have been put into developing alternative NMDAR antagonists with similar antidepressant efficacy and reduced psychotomimetic adverse effects, none of the drugs tested matched the full therapeutic potential of ketamine and accumulating evidence suggests that its psychoactive actions may involve additional mechanisms.
Beyond receptor blockade, we propose that ketamine dynamically reshapes the subsynaptic distribution of NMDAR and thereby modulates the plastic range and wiring of corticomesolimbic networks supporting reward and mood to alleviate the symptoms of depression. To explore this hypothesis, we will delve into the action mechanisms of ketamine at the single molecule level. Using combined skills in super-resolution imaging, electrophysiology and biochemistry, we will assess the impact of ketamine, its isomers ((R)- and (S)-ketamine) and metabolites ((2R,6R)- and (2S,6S)-hydroxynorketamine) on the surface dynamics and synaptic stabilization of NMDAR in cortical and hippocampal networks. Using a mouse model of depression based on chronic corticosterone administration, we will then explore how ketamine-elicited NMDAR redistributions may support connectivity changes in corticomesolimbic networks and implement behavioral and pharmacological readouts to establish whether modulating the synaptic organization of NMDAR counteracts or mimicks the antidepressant or psychotomimetic actions of ketamine. Conducting this ambitious and interdisciplinary project within a consortium of great complementarity - gathering internationally recognized expertise in the fields of cellular and molecular neuroscience, neurophotonics, pharmacology and behavior - will allow us to determine whether the action of ketamine on mental states may start with synaptic reorganizations of NMDAR at the nanoscale.