Intranasal Delivery of Ketamine Induces Cortical Disinhibition

Abstract

Our previous studies find that subcutaneously administered (s.c.) subanesthetic ketamine promotes sustained cortical disinhibition and plasticity in adult mouse binocular visual cortex (bV1). We hypothesized that intranasal delivery (i.n.) of subanesthetic ketamine may have similar actions. To test this, we delivered ketamine (10 mg/kg; i.n.) to adult mice, and then recorded excitatory pyramidal neurons or PV+ interneurons in L2/3 of bV1 slices. In pyramidal neurons the baseline IPSC amplitudes from mice treated with ketamine are significantly weaker than in control mice. Acute bath application of neuregulin-1 (NRG1) to cortical slices increases these IPSC amplitudes in mice treated with ketamine but not in controls. In PV+ interneurons the baseline EPSC amplitudes from mice treated with ketamine are significantly weaker than in control mice. Acute bath application of NRG1 to cortical slices increases these EPSC amplitudes in mice treated with ketamine but not in controls. We also find that mice treated with ketamine exhibit increased pCREB staining in L2/3 of bV1. Together, our results show that a single intranasal delivery of ketamine reduces PV+ interneuron excitation, and reduces pyramidal neuron inhibition, and that these effects are acutely reversed by NRG1. These results are significant as they show that intranasal delivery of ketamine induces cortical disinhibition, which has implications for the treatment of psychiatric, neurologic, and ophthalmic disorders.

Significance Statement We show that intranasal delivery of a single subanesthetic dose of ketamine in the mouse model has profound effects on the microcircuitry in sensory cortex. We find that intranasal delivery of ketamine reduces parvalbumin-expressing interneuron (PV) excitation and reduces pyramidal neuron inhibition. Disinhibition is a critical step for promoting cortical neuroplasticity by ketamine therapy. Despite the very important clinical use of intranasal ketamine, surprisingly few publications have reported using this route of administration in animal models for translational research. Here, we show how intranasal ketamine modulates the circuitry to bring about cortical disinhibition.