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

• 成果类型: Article
• 署名作者: Adam, Elie; Kowalski, Marek; Akeju, Oluwaseun; Miller, Earl K.; Brown, Emery N.; McCarthy, Michelle M.; Kopell, Nancy
• 署名单位: Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Boston University; Harvard University; Harvard Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9315
• DOI: 10.1073/pnas.2402732121
• 发表日期: 2024-05-28
• 关键词: interneurons; neurons; slow; inhibition; glutamate; cortex; vip

摘要

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 GABAreceptor-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.