ReviewRedox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology?
Introduction
Schizophrenia is considered a disorder with an important neurodevelopmental component. Various genetic and environmental risk factors can affect brain developmental processes including maturation of interneurons and oligodendrocytes, which could eventually contribute to the emergence of the symptoms during adolescence and early adulthood (Insel, 2010). Our current understanding of the neurobiological processes involved in schizophrenia remains, however, limited. Many hypotheses have been proposed, but a consensus among the research community is lacking. Prominent hypotheses include disturbance of glutamatergic neurotransmission in the form of hypofunction of NMDA receptors (NMDARs) (Krystal et al., 1994, Coyle et al., 2012, Kantrowitz and Javitt, 2012, Steiner et al., 2013), neuroinflammation (Saetre et al., 2007, Potvin et al., 2008, van Berckel et al., 2008, Meyer, 2013), and redox dysregulation (Do et al., 2009a, Do et al., 2009b, Clay et al., 2011, Gysin et al., 2011, Martins-de-Souza et al., 2011, Yao and Keshavan, 2011). We propose that dysregulation of redox homeostasis, neuroimmune, and glutamatergic systems induced by different etiological factors constitute, via their reciprocal interactions, one “central hub” as a common final pathway contributing to this disorder (Fig. 1). Here, we review the effect of dysregulation of each of these systems and their interactions on excitatory/inhibitory balance of local neuronal circuits (microcircuits), as well as the connections between distant brain areas (macrocircuits). In particular, we propose that dysfunction in these systems has deleterious effects on normal development of cortical and hippocampal parvalbumin-expressing interneurons (PVIs), which are essential for fast local neuronal synchronization, and on oligodendrocytes, which form myelin sheets around axons providing fast signal conduction between the brain regions. Anomalies of PVIs and oligodendrocytes are indeed widely recognized in schizophrenia and considered to contribute to abnormal brain connectivity leading to cognitive, affective, and social deficits.
Section snippets
A “hub” formed by the redox, glutamatergic, and neuroimmune systems
A dysregulation of the redox, glutamatergic, and neuroimmune systems has all been reported in schizophrenia. Genetic and/or environmental risk factors can contribute to disturbances within each of these tightly interdependent systems (see Fig. 1 and its legend for more details). In particular, redox pathways represent a central node via their numerous reciprocal interactions with the glutamatergic and immune systems. Oxidative stress is defined as an imbalance between antioxidants and
Parvalbumin interneurons
PVIs are GABAergic neurons that form inhibitory synapses onto either the cell body (for parvalbumin-expressing basket cells) or the axon initial segment (for parvalbumin-expressing chandelier cells) of pyramidal neurons (PNs). Basket cells control inputs reaching the soma of PNs, while chandelier cells control PN output. PVIs, which are interconnected via gap junctions (Fukuda et al., 2006) and reciprocal GABAergic synapses, constitute a cellular network able to synchronize the excitatory state
Evidence for impaired oligodendrocytes/myelination in schizophrenia
Oligodendrocytes and myelination are clearly impaired in schizophrenia (Davis et al., 2003, Takahashi et al., 2011, Chew et al., 2013). The observations supporting this claim include decreased expression of oligodendrocyte-related genes (Hakak et al., 2001, Tkachev et al., 2003, Katsel et al., 2005), impairment of oligodendrocyte maturation (Kerns et al., 2010), reduced number and/or density of oligodendrocytes in gray and white matter (Hof et al., 2003, Uranova et al., 2004, Byne et al., 2008
N-acetylcysteine, a potential therapeutic or prevention drug
Novel strategies aiming to regulate redox, immune, and glutamatergic systems could therefore be potentially useful to prevent or attenuate developmental anomalies yielding schizophrenia pathophysiology. To date, clinical trials using molecules targeting either the glutamatergic system (mGluR5, mGluR2/3, glycine site of NMDARs) (Javitt, 2012, Kantrowitz and Javitt, 2012, Poels et al., 2014, Vinson and Conn, 2012), the immune (Muller et al., 2013, Leza et al., 2015), or antioxidant systems (Reddy
Concluding remarks
Brain development is dependent upon sequences of events: proliferation, differentiation, migration, formation, and maturation of neuronal circuitry. The pace of development varies among brain structures, with the prefrontal cortex being the last to mature. Brain maturation mechanisms are under genetic control and influenced by environmental insults, suggesting that different brain regions could be vulnerable to a dysregulation of the “hub” during specific developmental periods. For instance,
Role of funding source
The funding sources had no role in decision to publish or preparation of the manuscipt.
Contributors
PS wrote the drafts of the manuscript; JHC, AM, DD, POD, MC, and KQD contributed to the writing of the manuscript and approved its final version.
Conflict of interest
P. O. is an employee and stockholder of Pfizer, Inc. All other authors declare no conflict of interest.
Acknowledgments
We thank our financial supports: Swiss National Science Foundation (# 31-116689 to KQD and # 310030_135736/1 to KQD and PS), National Center of Competence in Research (NCCR) “SYNAPSY — The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (no. 51AU40_125759 to KQD), Avina Foundation, Damm-Etienne Foundation, “Loterie Romande”, and Alamaya Foundation. Dr. O'Donnell was supported by the University of Maryland School of Medicine and by the National Institute of Mental
References (231)
- et al.
Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli
Neuron
(2012) - et al.
N-acetylcysteine—a safe antidote for cysteine/glutathione deficiency
Curr. Opin. Pharmacol.
(2007) - et al.
Electrophysiological intermediate biomarkers for oxidative stress in schizophrenia
Clin. Neurophysiol.
(2013) - et al.
N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial
Biol. Psychiatry
(2008) - et al.
The promise of N-acetylcysteine in neuropsychiatry
Trends Pharmacol. Sci.
(2013) - et al.
The immune system and developmental programming of brain and behavior
Front. Neuroendocrinol.
(2012) - et al.
Nonsteroidal anti-inflammatory treatment prevents delayed effects of early life stress in rats
Biol. Psychiatry
(2011) The environment and susceptibility to schizophrenia
Prog. Neurobiol.
(2011)- et al.
Psychopathology and the human connectome: toward a transdiagnostic model of risk for mental illness
Neuron
(2012) - et al.
Redox activation of Nrf2 & NF-kappaB: a double end sword?
Cell. Signal.
(2013)
Effects of mental illness and aging in two thalamic nuclei
Schizophr. Res.
Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: relevance to schizophrenia
Neurobiol. Dis.
Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine
Biol. Psychiatry
Free radicals and the pathobiology of brain dopamine systems
Neurochem. Int.
Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia
Int. J. Dev. Neurosci.
Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis
Lancet Neurol.
N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development
Biol. Psychiatry
Development of GABA and calcium binding proteins immunoreactivity in the rat hippocampus following neonatal anoxia
Neurosci. Lett.
Redox dysregulation, neurodevelopment, and schizophrenia
Curr. Opin. Neurobiol.
Minocycline attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain
Neuroscience
Interleukin-1beta-induced brain injury in the neonatal rat can be ameliorated by alpha-phenyl-n-tert-butyl-nitrone
Exp. Neurol.
The gamma cycle
Trends Neurosci.
Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior
Neuron
Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway
Biol. Psychiatry
Neuregulin rescues PC12-ErbB4 cells from cell death induced by H(2)O(2). Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase
J. Biol. Chem.
Genetic polymorphisms of glutathione S-transferases GSTM1, GSTT1, GSTP1 and GSTA1 as risk factors for schizophrenia
Psychiatry Res.
Synaptic energy use and supply
Neuron
Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia
Biol. Psychiatry
Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood
Behav. Brain Res.
Redox regulation of cytokine-mediated inhibition of myelin gene expression in human primary oligodendrocytes
Free Radic. Biol. Med.
Neonatal lipopolysaccharide induces pathological changes in parvalbumin immunoreactivity in the hippocampus of the rat
Behav. Brain Res.
A role for l-type calcium channels in the maturation of parvalbumin-containing hippocampal interneurons
Neuroscience
Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons
Biol. Psychiatry
Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats
Psychopharmacology
H2O2 signaling in the nigrostriatal dopamine pathway via ATP-sensitive potassium channels: issues and answers
Antioxid. Redox Signal.
Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion
J. Neurosci.
The origin and neuronal function of in vivo nonsynaptic glutamate
J. Neurosci.
Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks
Nat. Rev. Neurosci.
Glutathione peroxidase-catalase cooperativity is required for resistance to hydrogen peroxide by mature rat oligodendrocytes
J. Neurosci.
Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase
Science
Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia
J. Neurosci.
Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes
Nat. Neurosci.
A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E + C in schizophrenia
Transl. Psychiatry
Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex
J. Neurosci.
Intracellular redox state alters NMDA receptor response during aging through Ca2 +/calmodulin-dependent protein kinase II
J. Neurosci.
Thinking outside the cleft to understand synaptic activity: contribution of the cystine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling
Pharmacol. Rev.
Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia
World J. Biol. Psychiatry
Perineuronal nets protect fast-spiking interneurons against oxidative stress
Proc. Natl. Acad. Sci. U. S. A.
Brain injury induced by intracerebral injection of interleukin-1beta and tumor necrosis factor-alpha in the neonatal rat
Pediatr. Res.
Early-life iron deficiency anemia alters the development and long-term expression of parvalbumin and perineuronal nets in the rat hippocampus
Dev. Neurosci.
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