Ketamine potentiates a central glutamatergic presynapse

Ketamine rapidly and persistently increases glutamate release from presynaptic terminals in a cerebellar synapse, an effect that lasts more than 30 minutes after the drug is removed. This enhancement results from increased calcium influx and a greater number of vesicles ready for release. Another NMDAR blocker, MK-801, did not affect glutamate release, indicating a mechanism distinct from postsynaptic NMDAR blockade. The findings reveal a rapid presynaptic action of ketamine that may inform the development of faster-acting antidepressants.

Study at a glance

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.