Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors

Ketamine, an NMDA-receptor antagonist, produces sedation, analgesia, and dissociation at low doses and unconsciousness at high doses, generating gamma oscillations (>25 Hz) in the EEG at both doses, with slow-delta oscillations (0.1-4 Hz) interrupting gamma at high doses. Using a biophysical model of cortical circuits, the authors show how NMDA-receptor antagonism by ketamine leads to disinhibition in neuronal circuits, and how the disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition generates gamma oscillations at both doses and slow-delta oscillations at high doses. This work reveals general mechanisms for oscillatory brain dynamics distinct from previous reports and offers insights into ketamine's action as an anesthetic and therapy for treatment-resistant depression.

Study at a glance

Abstract

Ketamine is an 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 (0.1-4 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 non-human primate local field potential recordings. We have discovered 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.