Ketamine potentiates a central glutamatergic presynapse
Abdelmoneim Eshra, Noa Lipstein, Stefan Hallermann
bioRxiv Preprint Server December 17, 2023 preprint DOI: 10.1101/2023.12.17.571741 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Cerebellar synapse |
| Interventions | Ketamine MK-801 |
| Duration | Within minutes, persisting >30 minutes after washout |
| Topics | Esketamine Ketamine |
| Keywords | Ketamine: ketamine Dissociative anesthetic Antidepressant drug Antidepressants: antidepressants Depression treatment Mood elevators Psychiatric drugs Psychotropic medications Neuroscience: neuroscience Neurobiology Brain research Neuropharmacology Glutamate: glutamate Neurotransmission Excitatory neurotransmitter Pharmacodynamics Drug effects Molecular mechanism Signaling pathways |
| Citations | 1 |
| Key findings | Ketamine rapidly increases presynaptic glutamate release by enhancing calcium influx and the number of release-ready vesicles, an effect not produced by another NMDAR blocker. |
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.