Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology?

Abstract

Accumulating evidence points to altered GABAergic parvalbumin-expressing interneurons and impaired myelin/axonal integrity in schizophrenia. Both findings could be due to abnormal neurodevelopmental trajectories, affecting local neuronal networks and long-range synchrony and leading to cognitive deficits. In this review, we present data from animal models demonstrating that redox dysregulation, neuroinflammation and/or NMDAR hypofunction (as observed in patients) impairs the normal development of both parvalbumin interneurons and oligodendrocytes. These observations suggest that a dysregulation of the redox, neuroimmune, and glutamatergic systems due to genetic and early-life environmental risk factors could contribute to the anomalies of parvalbumin interneurons and white matter in schizophrenia, ultimately impacting cognition, social competence, and affective behavior via abnormal function of micro- and macrocircuits. Moreover, we propose that the redox, neuroimmune, and glutamatergic systems form a “central hub” where an imbalance within any of these “hub” systems leads to similar anomalies of parvalbumin interneurons and oligodendrocytes due to the tight and reciprocal interactions that exist among these systems. A combination of vulnerabilities for a dysregulation within more than one of these systems may be particularly deleterious. For these reasons, molecules, such as N-acetylcysteine, that possess antioxidant and anti-inflammatory properties and can also regulate glutamatergic transmission are promising tools for prevention in ultra-high risk patients or for early intervention therapy during the first stages of the disease.

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia

“…As discussed above, oxidative stress or redox dysregulation contribute crucially to PVI and myelin impairment in SZ. Moreover, as reviewed in Steullet et al, 125 dysregulation of redox homeostasis is fully reciprocal to neuroinflammation and NMDA-R hypofunction (figure 2). This triad constitutes one central pathophysiological "hub" upon which various genetic and environmental risk factors converge during neurodevelopment, leading to structural and functional connectivity impairments.…”

“…This triad constitutes one central pathophysiological "hub" upon which various genetic and environmental risk factors converge during neurodevelopment, leading to structural and functional connectivity impairments. Drugs targeting the triadic hub of oxidative stress, neuroinflammation, or NMDA-R hypofunction 125 would be promising candidates to prevent deleterious effects on cortical and hippocampal PVI and oligodendrocytes/myelin. As such treatments (eg, omega-3, sulforaphane, NAC) should be applied in early phases of the illness, they should be devoid of serious side-effects.…”

Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model

“…PCP administration to rats results in reduced rates of oxygen uptake in mitochondria isolated from their brains 100 and a meta-analysis of 44 studies identified a total antioxidant status in serum and plasma as a state marker for first-episode psychosis. 101 For these reasons, molecules that possess antioxidant and anti-inflammatory properties may be useful as potential novel treatments the first stages of schizophrenia (for review see 102 ).…”

Dominant-Negative DISC1 Alters the Dopaminergic Modulation of Inhibitory Interneurons in the Mouse Prefrontal Cortex

“…This hypothesis has been driven by postmortem studies revealing altered interneuron-associated markers in brains of patients [5-12]. Several developmental, pharmacological, and genetic manipulations yield loss of interneuron markers such as expression of the calcium-binding protein parvalbumin (PV) in a distinct subset of neurons [13-26], and all these manipulations yield adult animals with a range of behavioral deficits [27]. These data suggest that early-life disruption can lead to long-lasting changes in PV interneurons, supporting the notion that abnormal interneurons can drive altered excitation/inhibition balance.…”