Elsevier

Neuropharmacology

Volume 57, Issue 3, September 2009, Pages 193-200
Neuropharmacology

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

https://doi.org/10.1016/j.neuropharm.2009.06.002Get rights and content

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 pro-oxidant 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 PV-interneurons 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, although 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 redox balance leading to schizophrenia symptoms in late adolescence and early adulthood.

Introduction

The pathophysiology of schizophrenia is complex and involves many different cortical and subcortical systems. In particular, fast-spiking parvalbumin (PV)-positive inhibitory neurons, which represent 5% of all cortical neurons, are strongly affected. Reduced expression of GAD67, the main isoform synthesizing GABA in brain, is one of the most replicated findings in schizophrenia postmortem brain studies (Benes and Berretta, 2001, Lewis et al., 2005), and single nucleotide polymorphisms in the regulatory region of Gad1 (the gene coding for GAD67) are associated with childhood onset of schizophrenia (Rapoport et al., 2005). The decrease in GAD67 occurs primarily in the subset of inhibitory interneurons expressing the calcium binding protein parvalbumin (Beasley and Reynolds, 1997, Hashimoto et al., 2003). This apparent “loss of GABAergic phenotype” in PV-interneurons led to the suggestion that dysfunction of these fast-spiking inhibitory interneurons may be a core feature of the disease (Lewis et al., 2005). Whether these deficiencies are a consequence or a cause of the disorder is, however, a matter of debate.

PV-interneurons are involved in the generation of gamma oscillations, which regulate working memory and information transmission between cortical areas (Salinas and Sejnowski, 2001, Bartos et al., 2007). In particular, synaptic inhibition from PV-interneurons controls the firing rates of pyramidal neurons, synchronizes spikes within populations of neurons, and participates in the development of executive functions associated with prefrontal brain regions (Kawaguchi and Kubota, 1993, Goldman-Rakic, 1999, Markram et al., 2004). PV-interneurons are a part of the network that generates oscillatory activity in the gamma range (Sohal et al., 2009, Cardin et al., 2009), suggesting that their dysfunction may account for the disruption in evoked gamma-frequency oscillations and as well as the cognitive deficits observed in schizophrenia (Gonzalez-Burgos and Lewis, 2008, Roopun et al., 2008, Uhlhaas et al., 2008).

Adult levels of executive function emerge relatively late in the postnatal development of primates (Alexander and Goldman, 1978) and probably of rodents (Bachevalier and Beauregard, 1993, Ba and Seri, 1995). In primates and rodents, the delay in achieving mature performance on executive function tasks correlates with the maturation of oscillatory activity in the gamma range and with the maturation of PV-interneuronal networks (Wilson et al., 1994, Rao et al., 2000, Doischer et al., 2008, Uhlhaas et al.,), consistent with the delayed maturation of PV-inhibitory circuits. Development of PV-synaptic contacts, which sculpt this inhibitory network throughout childhood and adolescence, is dependent on GAD67 synthesis and activity in rodents (Chattopadhyaya et al., 2007). Environmental insults affecting the development of this inhibitory network, e.g. by affecting GAD67 expression, may lead to the abnormal formation of synaptic contacts by these interneurons. Thus, the dependence on GAD67 expression could make the developing brain vulnerable to environmental inputs that through disruption of the normal development of this inhibitory circuit lead to psychiatric diseases in adulthood.

Section snippets

The NMDA receptor antagonist model of schizophrenia

Several animal models recapitulating aspects (endophenotypes) of schizophrenia have been developed. Among these, exposure to NMDA receptor (NMDA-R) antagonists such as phencyclidine (PCP), ketamine, and MK801 are widely used in adult animals as acute pharmacological models to study behavioral and neurochemical disruptions relevant to the disease (rev. in Mouri et al., 2007). Administration of PCP to rodents produces deficits in spatial working memory, in reversal learning, and in sustained

The role of superoxide in the persistent effects of NMDA-R antagonists

Although exposure to one injection of the NMDA-R antagonist ketamine does not lead to the loss of GABAergic phenotype of PV-interneurons, injections of ketamine on two consecutive days is sufficient to produce this loss (Behrens et al., 2008). Similar exposures to ketamine in rats lead to an enduring decrease of inhibitory tone in prefrontal cortex (Zhang et al., 2008), supporting the idea that repetitive exposures to NMDA-R antagonists produce enduring effects resembling those observed in

Mechanism of activation of Nox2 in neurons

One of the most consistent findings in schizophrenia patients is an imbalance in plasma and cerebrospinal fluid levels of cytokines (Muller et al., 2000). In particular, elevated plasma levels of IL-6 have been consistently reported in patients and first-degree relatives with mood disorders (Ganguli et al., 1994, Naudin et al., 1996, Nunes et al., 2005), and correlate with exacerbation of psychotic episodes (Ganguli et al., 1994, Naudin et al., 1996, Lin et al., 1998, Zhang et al., 2002, Kudoh

Neurodevelopmental origins of schizophrenia: activation of the IL-6/Nox2 pathway may alter the development of PV-interneurons

Mild developmental impairments caused either by a genetic predisposition or by immune activation during development are believed to contribute to the appearance of schizophrenic symptoms in early adulthood (Rapoport et al., 2005). There is a strong correlation between infections in mid-gestation and the incidence of schizophrenia in the offspring (reviewed in Brown, 2006, Patterson, 2008). Cytokine induction due to abnormal immune activation, or inflammation, derails normal brain development

Glutamate receptors and the GABAergic phenotype of PV-Interneurons

In common with other glutamatergic synapses, glutamate preferentially activates AMPA-type glutamate receptors in mature PV-interneurons. However, unlike receptors on pyramidal neurons, AMPA receptors on PV-interneurons do not express GluR2 subunits, making them highly Ca2+ permeable (Goldberg et al., 2003). Regarding group 1 metabotropic glutamate receptors, cortical and hippocampal PV-interneurons preferentially express mGluR5 (Cauli et al., 1997, van Hooft et al., 2000). On the other hand,

Redox dysregulation of NMDA-R mediated transmission in PV-interneurons

Inactivation of synaptic proteins through oxidation is a well-described phenomenon, and considered to be behind many of the derangements of the nervous system observed in disease states (Rowan et al., 2005, Butterfield, 2006, Satoh and Lipton, 2007). Regulatory redox sites have been found in many proteins that are key to glutamatergic neurotransmission including, serine-racemase that is responsible for the synthesis of the endogenous modulator of the glycine site in NMDA receptors (Mustafa

Summary

The evidence reviewed here points toward a precipitating oxidative period early in the development of PV-interneurons that, after a cascade of compensatory changes to other neurons, may leave the cortex in a highly vulnerable state. This may account for the long delay before the symptoms of schizophrenia appear in early adulthood, when synaptic reorganization, hormonal changes and environmental stresses could tip the balance toward the dysregulation of cortical circuits (Fig. 1). Only a few of

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