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Does Oxidative Stress Link NMDA and GABA Hypotheses of Schizophrenia?

9 December 2007. Could oxidative stress underlie the pathology of schizophrenia? A paper in the December 7 issue of Science reports that reactive oxygen species mediate some of the effects of the NMDA receptor antagonist ketamine on inhibitory interneurons. Researchers led by Margarita Behrens and Laura Dugan at the University of San Diego, La Jolla, California, demonstrate that activation of NADPH oxidase, an enzyme that generates the toxic reactive oxygen species superoxide, is crucial for ketamine-induced disruption of parvalbumin-expressing interneurons. These inhibitory neurons play a crucial role in regulating excitatory neural networks in the brain, and there is evidence that their activity is compromised in schizophrenia patients. As ketamine and other NMDA-type glutamate receptor blockers induce psychotic behaviors indistinguishable from those seen in schizophrenia patients, the finding raises the possibility that in schizophrenia, like many other nervous system disorders, neurons may be particularly susceptible to oxidative stress.

Linking neurotransmitter hypotheses of schizophrenia
Fast-spiking interneurons expressing the calcium-binding protein parvalbumin (PV) modulate cortical networks via their release of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter. Postmortem analysis shows that this neuronal phenotype is depleted in the cortex of patients with schizophrenia (see, for example, Beasley et al., 2002; Hashimoto et al., 2003). There is evidence that these particular interneurons have not been lost, but are merely producing less parvalbumin, along with producing less GAD67, a GABA-synthesizing enzyme that is also depleted in schizophrenia (see SRF related news story).

Linking these GABAergic phenomena with glutamatergic signaling via the NMDA receptor, Behrens and colleagues have previously shown that ketamine exposure also depletes interneurons in culture of parvalbumin and GAD67 (Kinney at al., 2006). This suggests that blocking NMDA signaling in GABAergic neurons causes a loss in GABA transmission, which in turn frees glutamatergic neurons from inhibitory innervation and leads to heightened glutamate release. By a hypothetical feedback mechanism, cortical neuronal networks would respond to the excess glutamatergic signaling by reducing the GABAergic signaling through parvalbumin expressing interneurons.

In support of this model, Behrens and colleagues now report that adding the GABA agonist muscimol to mouse neuronal cultures treated with ketamine—in effect, fooling the system into thinking that the GABAergic interneurons are performing normally—protects GABAergic neurons from parvalbumin and GAD67 loss.

Oxidative stress as an underlying mechanism?
But what is it about NMDA antagonists that could cause loss of PV and GABA in the first place? Researchers have recognized that NMDA antagonists cause an increase in reactive oxygen species both in vivo and in vitro (Xia et al., 2002; Zuo et al., 2007), though it is not clear why. But Behrens and colleagues, noting recent reports that NADPH oxidase is found in the brain, wondered if this enzyme may be involved. Recent evidence suggests that the enzyme may have unappreciated roles in cellular communication, but its primary role appears to be generation of highly toxic superoxide for the destruction of engulfed bacteria in phagocytes.

Several lines of evidence suggest that Behrens and colleagues may have identified a pathway crucial to the loss of parvalbumin and GAD67 expression in GABAergic interneurons. They report that prolonged exposure to low levels of ketamine drives superoxide production in primary neuronal cultures, and that both a superoxide scavenger (C3) and an NADPH oxidase inhibitor (apocynin) protect the PV/GAD67 phenotype from ketamine.

In the bottom left panel of the figure above (figure 4B from the article), ketamine produces a red cloud of superoxide in mouse prelimbic cortex, with an accompanying loss of parvalbumin reactivity (green). But pretreatment to reduce superoxide production preserves parvalbumin reactivity as seen in the panels on the right. [Image credit: Behrens et al., Science. 2007 December 7;318:1645-1647. Reprinted with permission from AAAS.]

More significant, perhaps, is that pretreatment with both the scavenger and inhibitor also prevent the effects of ketamine in live animals. Analysis of mouse prefrontal cortex, an area of the brain thought to be particularly important for the psychopathology of schizophrenia, showed that ketamine induces a widespread increase in superoxide, which can be abrogated by C3 or apocynin. The effects extend to the PV-positive interneurons, which retain their parvalbumin and GAD67 when animals are prophylactically protected.

All told, the authors hypothesize that, "NADPH oxidase may be a contributor to oxidative mechanisms involved not only in the psychotomimetic effects of NMDA-R antagonists, but also in schizophrenia and other processes involving increased oxidative stress in the brain.” The work also contributes to the ongoing debate about the induction of schizophrenia-like symptoms in healthy people who take NMDAR antagonists “recreationally” (see comment from John Krystal below).

It is also worth noting that other researchers have recently made a connection between schizophrenia and oxidative stress, namely, a genetic polymorphism in a gene needed for synthesis of the antioxidant peptide glutathione (see related SRF news). It could be that oxidative stress may play a much greater role in the disease than previously anticipated.—Tom Fagan.

Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan L. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Science. 2007 December 7;318:1645-1647. Abstract

Comments on News and Primary Papers
Comment by:  John Krystal, SRF Advisor
Submitted 6 December 2007 Posted 9 December 2007

The paper by Behrens and colleagues provides exciting new data to suggest that NADPH oxidase plays an important role in the impact of the NMDA receptor antagonist, ketamine, upon parvalbumin-containing (PVC) fast-spiking GABA interneurons. The authors show that ketamine causes an activation of NADPH oxidase, resulting in increases in superoxide production. The elevation in free radicals, presumably toxic to these neurons, is associated with reduction in the expression of parvalbumin and GAD67. These effects of ketamine could be prevented by inhibition of NADPH oxidase.

These data were interpreted by the authors to help explain the schizophrenia-like effects of ketamine in healthy humans. I think that these data provide important insights into the impact of reductions in NMDA receptor function, and they may be relevant to schizophrenia. First, the data amplify the implications of the work of Kinney, Cunningham, and others who have shown that PVC interneurons express the NR2A subunit of the NMDA receptor and that deficits in NMDA receptor function may contribute to reduced...  Read more

View all comments by John Krystal

Comment by:  Steven Siegel (Disclosure)
Submitted 6 December 2007 Posted 9 December 2007

The article by Behrens and colleagues provides evidence for a mechanistic link between NADPH oxidase and disruption of normal protein expression in some interneurons following the drug ketamine. Data presented demonstrate that addition of an NADPH oxidase inhibitor, given in the animal’s drinking water, blocked the effects of ketamine on a specific class of interneurons that contains parvalbumin. Several lines of research suggest that this population of cells is disrupted in schizophrenia, and that reductions of NMDA-type glutamate receptor activity may lead to that impairment. The important iterative advance in the current study links the reduction in NMDA receptor-mediated glutamate transmission to a specific intracellular mechanism and molecular pathway. Furthermore, the authors demonstrate that they can effectively block the cellular changes by inhibiting that pathway, suggesting a novel therapeutic target.

This leads to two major questions: 1) Could NADPH oxidase inhibitors, or similar mechanisms be used to avert the onset of schizophrenia if administered during a...  Read more

View all comments by Steven Siegel

Comment by:  Dan Javitt, SRF Advisor
Submitted 7 December 2007 Posted 10 December 2007

The study by Behrens and colleagues is an excellent illustration of how breaking with traditional paradigms can lead to identification of novel potential targets for intervention in schizophrenia. As detailed on the pages of Schizophrenia Research Forum (e.g., Interview with D. Lewis) and the cited articles from F. Benes, one of the most consistent findings in schizophrenia is the downregulation of PV and GAD67 expression in PV+ GABAergic interneurons. Dysfunction of these neurons, in turn, may be responsible for frontal neurocognitive and dopaminergic deficits. The underlying cause of the GABAergic interneuron changes, however, has only intermittently been investigated.

One of the leading potential mechanisms underlying reduced PV and GAD67 expression in brain in schizophrenia has always been NMDA dysfunction, given the strong expression of NMDA receptors on GABA interneurons, as described by Behrens and colleagues, and the well-known ability of NMDA antagonists to induce both symptoms and...  Read more

View all comments by Dan Javitt

Comment by:  Julie MarkhamJames I. Koenig
Submitted 10 December 2007 Posted 10 December 2007

The role of reactive oxygen species in the pathogenesis of schizophrenia is currently unclear. Several lines of evidence support a greater production of these reactive molecules in schizophrenia because of reduced levels of important buffers for superoxides, such as glutathione. Other research, however, suggests that antipsychotic drugs themselves increase the production of oxygen radicals. In this week’s issue of Science, Behrens and colleagues present data supporting the involvement of reactive oxygen species in the pathophysiology of schizophrenia. The authors have previously shown that administration of an NMDA receptor antagonist to primary cultures of cortical neurons results in the loss of GAD67 and parvalbumin (PV; a calcium-binding protein) from PV positive GABAergic interneurons (Kinney et al., 2006), similar to what has been observed in studies using postmortem tissue from patients with schizophrenia (e.g., Volk et al., 2000;   Read more

View all comments by Julie Markham
View all comments by James I. Koenig

Comment by:  Gavin Reynolds
Submitted 10 December 2007 Posted 10 December 2007

For two decades, following the work by Benes and her colleagues, it has been increasingly apparent that there is a deficit in cortical GABAergic neurons in schizophrenia. Ten years ago we found that the parvalbumin (PV)-containing, but not calretinin-containing, subgroup of these neurons was selectively affected, and recently this specific deficit has been seen in animal models of the disease. Repeated administration of non-competitive NMDA receptor antagonists such as PCP, MK801, and ketamine can induce in rats some behaviors reminiscent of schizophrenia, as well as enduring deficits in PV expression.

Behrens and colleagues have identified some of the molecular mechanisms underlying this specific neurotoxicity of ketamine and, probably, other NMDA antagonists. That the effects of ketamine involve generation of reactive oxygen species (ROS) is not surprising, given the ubiquity of oxidative free radical production in neurotoxic processes. However, identifying the role of NADPH oxidase in producing ROS in response to ketamine, and demonstrating that this process determines...  Read more

View all comments by Gavin Reynolds

Comment by:  Kenneth Johnson
Submitted 18 December 2007 Posted 18 December 2007

The recent study by Behrens and colleagues provides in vitro evidence that blockade of NMDA receptors by ketamine leads to a selective reduction in PV and GAD67 that appears to be due to the toxic effects of superoxide anion arising subsequent to the activation of NADPH oxidase. Blockade of the sublethal, toxic effects of ketamine in neuronal culture is consistent with our report demonstrating that the apoptotic effect of phencyclidine (PCP) on cortical neurons in vivo also could be prevented by the superoxide dismutase mimetic, M40403 (Wang et al., 2003). Though seemingly non-specific, superoxide dismutase mimetics may prove to be useful in the treatment of ketamine or PCP-induced psychosis because of the relative sparseness of critical life-promoting processes that require superoxide anion. Perhaps more importantly, a better understanding of the mechanisms underlying ketamine-induced loss of PV/GAD67 may lead to novel treatment modalities for schizophrenia.

While the primary focus of the report by Behrens and colleagues is on...  Read more

View all comments by Kenneth Johnson

Comment by:  Patricia Estani
Submitted 11 January 2008 Posted 13 January 2008
  I recommend the Primary Papers
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