FIG. 5.

Oxidative stress induced by repetitive NMDAR blockade leads to loss of phenotype in parvalbumin-positive (PV+) neurons. Exposure of NMDARs to noncompetitive antagonists, such as ketamine, induces a preferential blockade of NMDARs in PV+ neurons (left), which disinhibits pyramidal neurons (right). Resultant excess of glutamate (Glu) release facilitates the production of interleukin-6 (IL-6), which in turn activates the NADPH oxidase Nox2 directly (short-term), as well as upregulates the expression of Nox2 (long-term). Elevated activity of Nox2 produces ROS that further promote glutamate release and eventually cause a dramatic downregulation of parvalbumin (PV) and GAD67 in PV+ neurons.