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

Redox dysregulation severely impacts the development of PV+ fast spiking interneurons.

“Interestingly, redox dysregulation severely impacts the development of PV+ fast spiking interneurons 81,83”

High metabolic demands make fast-spiking interneurons particularly vulnerable to oxidative stress.

“High metabolic demands render fast-spiking interneurons particularly vulnerable to oxidative stress (23).”

Animal models with globally disrupted redox state show defects in fast-spiking interneurons.

“Animal models of globally disrupted redox state exhibit defects in fast-spiking interneurons (16, 23, 25)”

High metabolic requirements of fast-spiking PV interneurons may readily generate reactive oxygen species when antioxidant systems are impaired, leading to breakdown of PNNs.

“The high metabolic requirements of the fast-spiking PV-interneuron (23) may readily generate reactive oxygen species when their antioxidant systems are impaired, leading to the breakdown of PNNs themselves (Figure 2C,D) (53).”

NMDAR blockade in adults disrupts excitatory/inhibitory balance in cortical circuits, affecting parvalbumin interneurons and neuronal network activity.

“Numerous studies show that NMDAR blockade in adults disrupts excitatory/inhibitory balance in cortical circuits, affecting PVI (Behrens et al., 2007) and neuronal network activity (Carlen et al., 2012; Homayoun and Moghaddam, 2007; Kocsis et al., 2013; Korotkova et al., 2010; Lazarewicz et al., 2010).”

Superoxide overproduction by NADPH oxidase is deleterious to parvalbumin interneurons, and NOX inhibition prevents the parvalbumin interneuron impairment induced by social isolation.

“Furthermore, superoxide overproduction by NADPH oxidase (NOX) is also deleterious to PVI (Behrens et al., 2007), and NOX inhibition prevents the PVI impairment induced by social isolation (Schiavone et al., 2009).”

Animal models of schizophrenia show reduced PV fluorescence per cell in prelimbic regions.

“Animal models that mimic schizophrenia replicate the loss of PV-INs in the hippocampus [6,14,15], and show a loss of PV fluorescence per cell in prelimbic regions [16].”

This PV-IN injury is linked to IL-6-mediated, Nox2-dependent NADPH oxidase activation and superoxide production.

“This injury is connected to IL-6mediated Nox2-dependent NADPH oxidase activation and production of superoxide [16,95].”

PV-INs receive the greatest excitatory input of any inhibitory neuron population in the cortex, placing them under intense stress.

“Indeed, PV-INs receive the greatest excitatory input of any population of inhibitory neurons in the cortex, which puts them under intense stress [16,80].”

PV-INs have extraordinary energy requirements to support high metabolic activity and to protect against significant glutamatergic stress.

“PV-INs have extraordinary energy requirements to support a high metabolic activity and to protect against significant glutamatergic stress [16,80,81].”

Ketamine, a pro-inflammatory stimulus, injures PV-INs in vitro and in vivo.

“For example, the NMDA receptor antagonist ketamine, a pro-inflammatory stimulus, injures PV-INs in vitro and in vivo [16,95].”

The oxidative stress-induced PVI deficit may also hold for other brain regions like the hippocampus, as shown in some models of schizophrenia (e.g., GCLM KO, ketamine, MAM, poly(I:C), and social defeat).

“Although our analysis focused on oxidative stress-induced PVI deficit in the prefrontal cortex, this deficit may also hold for other brain regions like the hippocampus, as shown in some models of schizophrenia (for example, GCLM KO, ketamine, MAM, poly(I:C) and social defeat.22, 37, 47, 48, 84”

Redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models.

“As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models.”

PVIs are vulnerable to redox dysregulation/oxidative stress.

“Indeed, PVIs are vulnerable to redox dysregulation/oxidative stress.37, 38, 39, 40”

Prolonged NMDA-receptor hypofunction is associated with reduced GABAergic neurotransmission.

“prolonged NMDA-receptor hypofunction is associated with reduced GABAergic neurotransmission, which has been confirmed in several studies”

Noncompeting NMDA antagonists affect inhibitory interneuron function by altering redox mechanisms, an effect that depends on interleukin 6 and other cytokines.

“Noncompeting NMDA antagonists affect inhibitory interneuron function by altering redox mechanisms, 74 an effect that depends on interleukin 6 and other cytokines.75”