Dissociation-related behaviors in mice emerge from the inhibition of retrosplenial cortex parvalbumin interneurons.

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.

Study at a glance

Abstract

Dissociation, characterized by altered consciousness and perception, underlies multiple mental disorders, but the specific neuronal subtypes involved remain elusive. In mice, we find that dissociation-inducing doses of ketamine significantly inhibit retrosplenial cortex (RSC) parvalbumin interneurons (PV-INs), enhancing delta oscillations (1-3 Hz) and delta-gamma phase-amplitude coupling (δ-γ PAC) and inducing dissociation-like behaviors. Optogenetic inhibition of RSC PV-INs triggers delta oscillations, δ-γ PAC, and some dissociation-like behaviors without ketamine. Furthermore, activation of RSC PV-INs or knockdown of the N-methyl-D-aspartate receptor subunit NR1 and the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in RSC PV-INs attenuates ketamine-induced delta oscillations, δ-γ PAC, and certain dissociation-like behaviors. These findings reveal that PV-INs regulate delta oscillations and δ-γ PAC and identify NR1 and HCN1 as ketamine targets in PV-INs that may cooperatively affect dissociation, possibly providing potential therapeutic targets for dissociative symptoms.