Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase

Repeated exposure to the anesthetic ketamine, which blocks NMDA receptors, causes a lasting increase in superoxide in the brain by activating NADPH oxidase in neurons. This increase in superoxide leads to dysfunction of fast-spiking inhibitory interneurons in the prefrontal cortex, specifically reducing their expression of parvalbumin and the GABA-producing enzyme GAD67—changes that mirror those seen in schizophrenia. Lowering superoxide production prevented these effects on inhibitory interneurons. The findings suggest that targeting NADPH oxidase could offer a new approach for treating ketamine-induced psychosis.

Study at a glance

Abstract

Abuse of the dissociative anesthetic ketamine can lead to a syndrome indistinguishable from schizophrenia. In animals, repetitive exposure to this N-methyl-d-aspartate-receptor antagonist induces the dysfunction of a subset of cortical fast-spiking inhibitory interneurons, with loss of expression of parvalbumin and the gamma-aminobutyric acid-producing enzyme GAD67. We show here that exposure of mice to ketamine induced a persistent increase in brain superoxide due to activation in neurons of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Decreasing superoxide production prevented the effects of ketamine on inhibitory interneurons in the prefrontal cortex. These results suggest that NADPH oxidase may represent a novel target for the treatment of ketamine-induced psychosis.