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.

Keywords: Development; Myelination; N-acetylcysteine; Oligodendrocytes; Oxidative stress; Parvalbumin interneurons.

Conflict of interest statement

Conflict of interest: P. O. is employee and stockholder of Pfizer, Inc. All other authors declare no conflict of interest.

Copyright © 2014 Elsevier B.V. All rights reserved.

Figures

Fig. 1

Proposed “hub” formed of the redox, neuroimmune, and glutamatergic systems whose dysregulation during development could disrupt maturation of parvalbumin interneurons (PVI) and oligodendrocytes, two cell types affected in schizophrenia and critical for short- and long-range neuronal network synchronization. This could impact structural and functional connectivity circuits affecting diverse aspects of cognitive, affective and social functioning (Buckholtz and Meyer-Lindenberg, 2012). Genetic risk factors combined with environmental insults can affect the homeostasis of one or several of the “hub” systems which in turn could impact the others through reciprocal interactions (reciprocal arrows). Genetic vulnerability to redox dysregulation in schizophrenia is supported by polymorphisms and copy number variations in genes related to the GSH metabolism (Gravina et al., 2011; Gysin et al., 2007; Mehta et al., 2013; Rodriguez-Santiago et al., 2010; Tosic et al., 2006). In addition, impaired function of proteins coded by other plausible risk genes, including DISC1, PROD, G72, NRG, DTNBP1, indirectly leads to oxidative stress often via mitochondrial dysfunction (Clay et al., 2011; Gokhale et al., 2012; Goldshmit et al., 2001; Johnson et al., 2013; Krishnan et al., 2008; Park et al., 2010). Genes related to the immune system have also been identified as potent risk genes for schizophrenia, in particular the major histocompatibility complex (MHC) genes, one of the most replicated genetic risk factors for schizophrenia disorder (Smyth and Lawrie, 2013; Stefansson et al., 2009). Finally, genetic vulnerability for NMDAR hypofunction seems to be more associated with potent risk genes encoding proteins that indirectly influence the function of this receptor; this includes d-amino acid oxidase, G72, dysbindin, and neuregulin (see Coyle et al., 2012), mGluR5 and proteins belonging to the postsynaptic NMDAR complex (Fromer et al., 2014; Kirov et al., 2012; Purcell et al., 2014; Timms et al., 2013). Developmental insults that are known to increase the risk for schizophrenia cause redox dysregulation/oxidative stress (Do et al., 2009b; Walter et al., 2002) and/or neuroinflammation (Brenhouse and Andersen, 2011; Garate et al., 2013; Kaur et al., 2013; Schiavone et al., 2009). Note that the dopaminergic or serotoninergic (5-HT) systems (and others = X Y) modulated by risk-factor genes and environment could also impact micro- and macrocircuits either directly or indirectly via interactions with the above “hub”. Dotted arrows depict impact of genetic risk factors. E/I balance: excitatory/inhibitory balance; PNN: perineuronal net surrounding PVI.

Fig. 2

The timing of environmental insults levied upon an individual (at risk) during his development, may determine which brain region microcircuits and which macrocircuits connecting distant brain areas are structurally and functionally affected. The period(s) of vulnerability of a micro- or macrocircuit may vary according to the genetic risk factors and the nature of the environmental stress and may be influenced by the developmental trajectory of other brain areas. In addition, microcircuits might be particularly susceptible prior to their final maturation during the period of enhanced plasticity. Therefore, the timing of environmental insults during development combined with specific genetic vulnerability could differentially affect circuit connectivity associated with sensory-motor function, social competence, affective behavior, and cognition leading to heterogeneous clinical phenotypes. An early insult could lead to more severe and wide-spectrum clinical phenotypes than a later insult.