Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

Abstract

An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

On the functions, mechanisms, and malfunctions of intracortical contextual modulation

“…In addition to that, Behrens and Sejnowski (2009) have reviewed evidence suggesting that dysregulation of PV interneurons in the developing cortex could explain the late onset of schizophrenic symptoms as well as the differences between the effects of brief and prolonged exposure to NMDA antagonists (Jentsch and Roth, 1999). Questions remain, however, as to exactly how PV interneurons are involved in the downstream effects of reduced activity at NMDARs (Gonzalez-Burgos & Lewis, 2012).…”

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…An abnormal increase in the oxidation state of these inhibitory neurons may be responsible for the onset of schizophrenia. 14,15 Dysregulation of the redox signaling pathway may provide an explanation for the developmental origins of schizophrenia because there appears to be a link between maternal viral infection during gestation and the incidence of this disease in the offspring. In rat models that reproduce this phenomenon, the developmental defects induced by such inflammatory responses are caused by activation of redox signaling.…”

Doxycycline Ameliorates Schizophrenia-Like Behaviors in Experimental Models in Mice by Targeting Underlying Oxidative Stress

“…Besides, accumulating evidence shows that ketamine also bind to other allosteric sites in the brain, such as phencyclidine-binding site within the NMDA receptor channel complex [40] and dopamine-D 2 receptor binding sites in the hippocampus [41]. However, the findings from Chindo et al [19] suggest that ketamine-enhanced immobility in the FST might be Evidence derived supports oxidative stress in the pathophysiology of schizophrenia [45]. In fact, accumulating body of evidences has reportedly demonstrated increase in the concentrations of oxidative stress parameters after treatment with classical antipsychotics such as, haloperidol [7] [8] [15] [46]; and that treatments with antioxidants like vitamin E lowered the levels of reactive oxygen species (ROS) and protected the cells.…”

“…From the glutamate-cycle, prolonged oxidative stress and immune alterations reduces the capacity of astrocytes to import glutamate, facilitating an increased extracellular glutamate levels [15] [30] [45]. Oxidative stress increased glutamate levels can inhibit cystine uptake by the cysteine/glutamate exchange system thereby causing intracellular GSH depletion, and consequently poor NMDA surface expression that results in NMDA hypofunctionality [34]; leading to decrease glutamate-dopamine modulations, that is, at least partly, mediated by decreased GSH signaling [49].…”