Ketamine blocks bursting in the lateral habenula to rapidly relieve depression
Cui, Y., Dong, Y., Hu, H., Ma, S., Ni, Z., Sang, K., Yang, Y.
This animal study (n=500) investigated the neural circuitry underlying the antidepressant efficacy of ketamine (10 -; 25mg/kg) in rodents and found that it blocks the activity of the lateral habenula, a network that normally inhibits reward processing, whose inhibition is in turn unblocked via ketamine.
Abstract
Introduction: The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive.Methods/Results: Here we show that blockade of NMDAR-dependent bursting activity in the ‘anti-reward center’, the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects.Discussion: Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.