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

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. [Display omitted] •RSC PV-IN inhibition triggers δ-γ PAC and a subset of dissociation-like behaviors•Optogenetic activation of RSC PV-INs mitigates ketamine’s dissociative effects•NR1 and HCN1 in PV-INs mediate certain ketamine-induced dissociative effects Dissociation is an altered state of consciousness marked by a disconnect from thoughts and feelings. Hu et al. manipulated RSC PV-INs, as well as their NR1 and HCN1 channels, regulating δ-γ PAC and modulating dissociation-related behaviors in mice, suggesting potential therapeutic targets.