Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors.
Elie Adam, Marek Kowalski, Oluwaseun Akeju, Earl K Miller, Emery N Brown, Michelle M McCarthy, Nancy Kopell
Proceedings of the National Academy of Sciences of the United States of America May 28, 2024 DOI: 10.1073/pnas.2402732121 via PubMed
Summary
AI-generated from the abstractKetamine, an NMDA-receptor antagonist, produces sedation and dissociation at low doses and unconsciousness at high doses, while generating gamma oscillations (>25 Hz) in the EEG that are interrupted by slow-delta oscillations (0.1–4 Hz) at high doses. Using a biophysical model of cortical circuits, the authors show how NMDA-receptor antagonism leads to disinhibition in neuronal circuits, and how disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition produces gamma oscillations at both doses and slow-delta oscillations at high doses. This work reveals general mechanisms for generating oscillatory brain dynamics and provides insights into ketamine's actions as an anesthetic and therapy for treatment-resistant depression.
Study at a glance
| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Keywords | Nmda-receptor antagonism Antidepressant effect Biophysical mechanisms Gamma oscillations Slow-delta oscillations |
| Citations | 30 |
| Key finding | Impaired NMDA-receptor kinetics cause disinhibition that, through interaction with GABA-receptor-mediated inhibition, produces gamma oscillations at high and low doses of ketamine and slow-delta oscillations at high doses. |
Abstract
Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.