Distinct synaptic mechanisms drive the behavioral response to acute stress and rapid correction by ketamine.

Ketamine, a rapidly acting antidepressant, works by restoring glutamate signaling in the hippocampus, countering the effects of a drug that induces depressed mood. Physostigmine, which triggers depression-like symptoms in humans, was found to cause long-term reduction of glutamate release in the mouse hippocampus. Ketamine rapidly re-establishes synaptic efficacy through postsynaptic signaling and masks the behavioral effects of physostigmine. The findings reveal that the synaptic mechanisms underlying mood changes differ from those behind antidepressant action, suggesting distinct pathways for neuropsychiatric disorders and their treatment.

Study at a glance

Abstract

Prevailing hypotheses on the mechanisms of antidepressant action posit that antidepressants directly counteract deficiencies in major neurotransmitter signaling systems that underlie depression. The rapidly acting antidepressant ketamine has been postulated to correct excess glutamatergic signaling via glutamatergic antagonism leading to the rescue of neuronal structural deficits and reversal of behavioral symptoms. We studied this premise using systemic administration of the acetylcholinesterase inhibitor physostigmine, which has been shown to rapidly elicit a shorter-term period of depressed mood in humans via cholinergic mechanisms. We observed that physostigmine induces acute stress in tandem with long term depression of glutamate release in the hippocampus of mice. However, ketamine rapidly acts to re-establish glutamatergic synaptic efficacy via postsynaptic signaling and behaviorally masks the reduction in passive coping induced by physostigmine. These results underscore the divergence of synaptic signaling mechanisms underlying mood changes and antidepressant action and highlight how distinct synaptic mechanisms may underlie neuropsychiatric disorders versus their treatment.