In mice, doses of ketamine that cause dissociation inhibit parvalbumin interneurons (PV-INs) in the retrosplenial cortex (RSC), increasing delta oscillations (1-3 Hz) and delta-gamma phase-amplitude coupling (δ-γ PAC) and producing dissociation-like behaviors. Directly inhibiting these neurons without ketamine also triggers delta oscillations, δ-γ PAC, and some dissociation-like behaviors. Activating RSC PV-INs or knocking down the NMDA receptor subunit NR1 and the HCN1 channel in these neurons reduces ketamine-induced delta oscillations, δ-γ PAC, and certain dissociation-like behaviors. The findings identify NR1 and HCN1 as ketamine targets in PV-INs that may cooperatively affect dissociation, suggesting potential therapeutic targets for dissociative symptoms.
Ketamine produces rapid antidepressant effects by both blocking NMDA receptors and increasing serotonin levels through inhibition of the serotonin transporter (SERT). A cryogenic electron microscopy structure shows ketamine binding to SERT's central site. The elevated serotonin activates vasoactive intestinal peptide (VIP)-expressing interneurons, a cell type essential for ketamine's rapid effects. Inhibiting these neurons blocks the antidepressant actions, identifying a specific neural pathway. This dual mechanism offers potential strategies for developing rapidly acting antidepressants.