How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Abstract

Significance: Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma-aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). Recent Advances: Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. Critical Issues: Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. Future Directions: The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia.

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

“…However, PVI are especially vulnerable to NMDAR hypofunction during development (Abekawa et al, 2007; Powell et al, 2012; Wang et al, 2008; Wang et al, 2013). Inhibition of NMDARs during early life causes a persistent decrease in number of parvalbumin-immunoreactive cells without cell death (Powell et al, 2012), suggesting that disruption of NMDAR-mediated signaling impairs maturation of these cells.…”

Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

“…More precisely, since NMDARs play a key role in mediating long-term potentiation and other synaptic modifications that are dependent on the level of neuronal activity, low activity due to inflammation or oxidative stress could lead to long-term changes in PVIs, especially given that the relative number of NMDA receptors is highest perinatally, presumably because they play a critical role in deciding which neurons mature, and which are pruned [15]. In line with this, even mild antagonism of NMDARs in rodents postnatally can lead to lasting alterations in PVI number [16,17]. Moreover, PVIs are the last subset of interneurons to develop, which may explain how the effects of oxidative stress and inflammation (which are thought to be involved in the pathogenesis of many illnesses) may lead to the particular alterations seen in schizophrenia [7,18,19].…”

“…For example, depletion of GSH postnatally leads to lasting psychosis-like symptomatology [61]. Furthermore, GSH deficits can reduce NMDAR function, which may in turn lead to decreases in cortical PVI number [16,62]. Moreover, studies preventing the formation of GSH through genetic modification of its biosynthetic enzyme, glutamate cysteine ligase (GCL) show oxidative stress that precedes PVI deficits, leading to long-term prefrontal and hippocampal PVI abnormalities with loss of synchronicity in high-frequency firing, and prolonged plasticity of hippocampal PVIs [63,64,65].…”

New Insights onNOXEnzymes in the Central Nervous System

“…However, interestingly, blockade of NMDA receptor by antagonists, such as ketamine, can also activate NOX2-dependent ROS in cortical neurons and lead to parvalbumin neuron depletion, a hallmark of psychiatric disease (180).…”