Ketamine potentiates a central glutamatergic presynapse
bioRxiv Preprint Server – December 17, 2023
Source: bioRxiv
Summary
Ketamine's rapid antidepressant action is counterintuitive: it blocks brain receptors yet boosts brain signaling. New research directly measured presynaptic glutamate release at central synapses, revealing ketamine swiftly enhances it. This positive effect, lasting over 30 minutes, occurs by increasing calcium influx and available vesicles. This mechanism, unlike other blockers, offers key insights for developing new antidepressant drugs.
Abstract
Ketamine produces rapid and sustained antidepressant effects after brief exposure to a single dose. Counterintuitively, while ketamine acts primarily as a blocker of postsynaptic N-methyl-D-aspartate receptors (NMDARs), increased signalling at glutamatergic synapses has been reported. Due to technical limitations, however, it remains unclear whether ketamine directly increases presynaptic glutamate release or acts via postsynaptic or network-level mechanisms. To address this knowledge gap, we used presynaptic capacitance measurements to directly monitor glutamate release in a cerebellar synapse. Ketamine increased glutamate release within minutes and this effect persisted >30 minutes after washout. MK-801, another NMDAR blocker, had no effect on glutamate release. Mechanistically, we show that the ketamine-mediated enhancement of presynaptic release results from an increase in both calcium influx and the number of release-ready vesicles. Our data uncover a rapid effect of ketamine on key presynaptic properties of central glutamatergic synapses, which has important implications for the development of antidepressant drugs.