Cortical interneurons, immune factors and oxidative stressas early targets for schizophrenia

Patricio O’DonnellDepartments of Anatomy & Neurobiology and Psychiatry, University of Maryland School of Medicine, 20 Penn St., Room S-251,Baltimore, MD 21201, USA

Keywords: adolescence, cognitive deficits, development, GABA, prefrontal cortex, schizophrenia

Abstract

Schizophrenia is a common disorder in which strong genetic predisposition is combined with environmental factors. Despite thewidely recognized developmental nature of the disease, symptoms do not emerge until late adolescence. Current therapeuticapproaches are therefore employed too late, as brain alterations may have been present earlier than symptom onset. Here I reviewthe developmental trajectory of the cortical circuits responsible for excitation–inhibition balance, which are at the center of currentpathophysiological views, and propose that oxidative stress in cortical interneurons may be a final common pathway by which severaldifferent etiological factors can yield the cortical dysfunction characteristic of schizophrenia. If this scenario is correct, redoxmodulators may be beneficial for the disease. It is critical that the developmental trajectories of the factors yielding oxidative stressare taken into account for those approaches to succeed.

Introduction

Schizophrenia (SZ) affects about 1% of the population worldwide, yetcurrent therapies have limited impact on many aspects of thisdevastating disorder. For decades, dopamine was central to patho-physiological views for schizophrenia, and all effective pharmacolog-ical approaches have in common a D2 dopamine receptor blockade(Seeman, 1987). However, although first- and second-generationantipsychotic drugs improve positive symptoms, they are marginallyeffective for negative symptoms and not at all effective for cognitivedeficits (Carpenter & Koenig, 2008). Cognitive deficits in SZ havereceived increasing attention, as they are a core feature of the diseaseand perhaps the strongest predictor of outcome (Green, 1996). Thelack of efficacy of current therapies on cognitive deficits is troubling,and has prompted several groups to seek other tools. As neurolepticsare ‘dirty drugs’ that target multiple receptors and their efficacyagainst psychotic symptoms was discovered serendipitously (Delay &Deniker, 1955), the past decades have witnessed the search for newpharmacological approaches based on preclinical research. GABA(gamma-aminobutyric acid) and glutamate neurotransmission emergedas critical elements in SZ pathophysiology (Coyle, 2004; Lewis et al.,2005; O’Donnell, 2011) and gained prominence in such efforts(Heresco-Levy et al., 1996; Patil et al., 2007). Both amino acidtransmitters are critical for the balance between excitation andinhibition necessary for proper prefrontal cortical activity andadequate cognitive functions (Lewis & Moghaddam, 2006). There-fore, it makes sense to target excitation–inhibition balance to treatcognitive deficits in SZ. Although some attempts have been made todevelop novel agents that target glutamate or GABA, the results havenot been impressive (Lewis et al., 2008). SZ is a disorder in dire need

of a new approach, and it is critical that any new direction is based onsolid preclinical science for it to be effective. Most importantly, thesenew approaches must consider the developmental trajectories of braincircuits implicated in SZ. Indeed, SZ has a clear genetic componentand is widely accepted as a neurodevelopmental disorder (Harrison &Weinberger, 2005), but symptoms do not become full blown until lateadolescence. Here, I review evidence of altered excitation–inhibitionbalance in SZ, the possible role of oxidative stress as a source ofinterneuron dysfunction and the developmental nature of these factors.Although most of the work reviewed relates to the prefrontal cortex(PFC), these alterations are likely to be present in other cortical areas,including allocortical regions such as the hippocampal formation.Novel therapeutic approaches could therefore include agents thattarget glutamate, GABA or oxidative stress, but the highest impactwill be achieved with early treatment, including the prodromal stage.

GABA and glutamate – the cortical interneuron story

A remarkable convergence of data from preclinical and clinical studiesidentifies cortical GABA interneurons as a critical element in SZpathophysiology. Non-competing NMDA (N-methyl-d-aspartate)receptor antagonists are widely used as a pharmacological model ofthe disease. These agents yield a state of cortical disinhibition (Coyle,2004; Homayoun & Moghaddam, 2007) that is thought to be related tocognitive deficits (Lewis & Moghaddam, 2006). It has been proposedthat NMDA antagonist-induced disinhibition is due to these com-pounds acting with higher affinity for NMDA receptors located ininhibitory interneurons (Coyle, 2004; Homayoun & Moghaddam,2007; Behrens & Sejnowski, 2009), but recent evidence indicatesNMDA currents in cortical interneurons may be negligible (Rotaruet al., 2011). Although it is possible that cortical disinhibition iselicited by effects of NMDA antagonists at a circuit level, it is evidentthat NMDA blockade can induce cellular changes in fast-spiking

Correspondence: Dr P. O’Donnell, as above.E-mail: podon002@umaryland.edu

Received 4 February 2012, revised 21 March 2012, accepted 22 March 2012

European Journal of Neuroscience, Vol. 35, pp. 1866–1870, 2012 doi:10.1111/j.1460-9568.2012.08130.x

ª 2012 The Author. European Journal of Neuroscience ª 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd

European Journal of Neuroscience

interneurons (Behrens et al., 2007), and knocking out NMDAreceptors from parvalbumin (PV) interneurons yields mice withseveral signs of a disinhibited cortex (Belforte et al., 2010). Thesedata strongly suggest that altered interneuron function is a criticalcomponent of the consequences of non-competing NMDA antago-nists. Another pharmacological model, sensitization to repeatedamphetamine, produces loss of PV interneuron labeling in theprelimbic PFC (Morshedi & Meredith, 2007). Amphetamine treatmentand NMDA receptor antagonism are interesting and useful models, butthe developmental aspects of the disease cannot be reproduced withpharmacological treatments in adult animals.

Among the several widely used developmental models, the neonatalventral hippocampal lesion (NVHL) stands out by producing diverseneurochemical, physiological and behavioral deficits resemblingphenomena observed in SZ with an onset during late adolescence(O’Donnell, 2011). The PFC in this model is also disinhibited due toimpaired GABA interneuron activation, as cortical interneuronscannot be efficiently activated by dopamine in this model (Tsenget al., 2008). PFC pyramidal neurons of adult NVHL rats presentexcess firing along with loss of interneuron-dependent beta oscilla-tions during a choice task (Gruber et al., 2010), indicating thedisinhibition is evident during behaviorally critical epochs. A medialPFC lesion reverses abnormal behaviors and altered physiologicalchanges in adult NVHL rats (Lipska et al., 1998; Goto & O’Donnell,2004), strongly suggesting the PFC is the critical brain regionresponsible for adult outcomes in the NVHL model.

Other developmental and genetic models also show evidence ofaltered interneuron function. Perinatal immune activation yields adultanimals with SZ-related anomalies. Treatment with the viral mimic polyI:C or the bacterial endotoxin lipopolysaccharide (LPS) during gestationresults in offspring with behavioral deficits when they become adults,including reduced prepulse inhibition of the acoustic startle responseand latent inhibition (Borrell et al., 2002; Shi et al., 2003; Meyer et al.,2006). Although interneuron function has not been assessed in thesemodels, neonatal LPS injections in the ventral hippocampus alteredadult cortical interneuron responses to dopamine (Feleder et al., 2010).Prenatal treatment with the antimitotic agent methylazoxymethanolacetate (MAM) yields a reduction in PV immunoreactivity in the PFCand ventral hippocampus of adult rats (Penschuck et al., 2006; Lodgeet al., 2009) along with a reduction in interneuron-dependent high-frequency electroencephalographic (EEG) oscillations (Lodge et al.,2009). Among genetic models, expression of a truncated disrupted-in-schizophrenia 1 (DISC1) gene that acts as a dominant negative duringdevelopment resulted in SZ-relevant abnormal behaviors and reductionin PV levels in adult mice (Hikida et al., 2007). Knocking down DISC1in the medial PFC via in utero electroporation of siRNA also resulted inabnormal behaviors with adult-onset and electrophysiological dataconsistent with loss of adult interneuron function (Niwa et al., 2010).Dysbindin is another candidate gene for SZ, and dysbindin knock-outmice exhibit fast-spiking interneurons with reduced excitability (Jiet al., 2009). Several of these models result in reduced PV staining incortical and hippocampal regions. These observations could be due toeither neuronal loss or reduced PV expression in neurons that are stillpresent. The latter is more likely, as reduced PV is not accompanied byloss of the GABA-synthesizing enzyme GAD67 in many of thesestudies (Behrens & Sejnowski, 2009; Lodge & Grace, 2009) and PV isan activity-dependent calcium-binding protein. Thus, several differentrodent developmental models have in common altered interneuronfunction, andwhenever the timingwas explored, this alteration emergedduring adolescence.

A causal role of interneuron dysfunction in SZ-relevant phenomenawas ascertained with genetic and pharmacological tools. A simple but

clever experiment testing whether intra-PFC blockade of GABA-Areceptors revealed that cognitive functions become impaired (Enomotoet al., 2011). Furthermore, selectively knocking down NMDA recep-tors in PV interneurons resulted in a wide array of SZ-relevant alteredbehaviors and electrophysiological changes (Belforte et al., 2010).These data indicate that altered interneurons in animal models of SZ canbe causal to behavioral deficits, reinforcing the notion that interneurondysfunction may be a central element in SZ pathophysiology.It is remarkable that the quite different manipulations involved in

the diverse SZ models have in common a deficit in interneuronfunction and that this deficit emerges during adolescence. Thisconvergence indicates that interneurons, and in particular PVinterneurons, are somewhat susceptible to insult from a variety ofdeleterious factors; the diversity of manipulations that can yieldinterneuron dysfunction and their different timing may reflect thevarious factors that may play a role in SZ etiology, which includecombinations of gene variations that alone confer a very small riskwith environmental factors. NMDA antagonism, gene manipulationsor developmental manipulations are useful tools to alter interneurondevelopment, but they should be considered as just tools. Although thenotion that NMDA receptors are abnormal in SZ has become populardue to the effects of NMDA antagonists, there is no unambiguoussupport for an NMDA deficit in the disease. NMDA blockade mayactually cause a downstream condition that mimics SZ pathophysiol-ogy without the need to have an actual NMDA deficit in the disorder.Also, the neonatal hippocampal lesion is a tool to yield altered PFCinterneurons and should not be interpreted as modeling hippocampalpathology. Genetic models are also reproducing risk factors, not thedisease. Not all SZ patients exhibit a truncated DISC1 gene, but whenDISC1 function is impaired during development, PFC circuits becomealtered. All these manipulations are tools that yield adult interneurondysfunction. Why are interneurons affected by such a diverse set ofconditions? Understanding the mechanisms that may affect thisvulnerable neuronal population at specific developmental points couldopen new possibilities on alternative approaches to treat SZ.

Immune factors and oxidative stress

Oxidative stress could play an important role in the biochemical basisof SZ as the mechanism that yields altered cortical interneurons.Oxidative stress results from an imbalance between reactive oxygenspecies (ROS) and antioxidants. Typical ROS include O2

) (superox-ide), H2O2 (hydrogen peroxide), NO (nitric oxide) and ONOO)

(peroxynitrite). Key enzymes that generate superoxide and NO arenicotinamide adenine dinucleotide phosphate (NADPH) oxidase andNO synthase (NOS) (Babior, 2004). Glutathione (GSH) and itsassociated enzymes are critical for the degradation of hydrogenperoxide (Meister & Anderson, 1983). GSH is a free radical scavengerand an inhibitor of lipid peroxidation that protects the brain fromoxidative stress (Janaky et al., 2007) and helps to regenerate otherantioxidants. Environmental factors, such as viral infections, inflam-mation and obstetrical complications, as well as psychological stressare tightly associated with an increase in oxidative stress (Liu et al.,1996; Lante et al., 2007) and are considered risk factors for SZ(Watson et al., 1984; Brown, 2006, 2011). It is therefore possible thatdisturbances of the mechanisms that maintain cellular homeostasisagainst oxidative damage may be involved in SZ pathology. It will bebeneficial to determine whether perinatal immune activation orconditions that yield oxidative stress during development result inaltered interneuron function.There is indeed some evidence of oxidative stress in SZ. Redox

alterations are associated with positive, negative and cognitive

Oxidative stress in interneurons and schizophrenia 1867

ª 2012 The Author. European Journal of Neuroscience ª 2012 Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 35, 1866–1870

symptoms in SZ (Do et al., 2009), and GSH synthesis is impaired inSZ patients (Do et al., 2000; Yao et al., 2006; Gysin et al., 2007).Furthermore, GSH levels were reduced in neuroleptic-free and treatedSZ patients and were inversely correlated with symptom severity(Raffa et al., 2009). The evidence indicates that oxidative stresscorrelates with SZ symptom clusters, but it needs to be determinedwhether this is a causal link and which brain circuits are affected byoxidative stress yielding such deficits.Animal models are useful tools to explore hypotheses such as

whether oxidative stress affects SZ-relevant behavioral outcomes.Studies indicate that markers of oxidative stress may be increased inseveral models of SZ; for example, PV-positive interneurons exhibitoxidative stress in the presence of NMDA receptor blockade (Behrenset al., 2007). Furthermore, it is likely that such oxidative stress isrelated to altered immune responses, as it cannot be observed in micedeficient in interleukin-6 (Behrens et al., 2008). Emerging evidencefrom our lab indicates that PV interneurons in NVHL rats exhibitoxidative stress prior to symptom onset. NVHL rats, but not shamcontrols, show increased levels of 8-oxo-7,8-dihydro-2¢-deoxyguano-sine (8-oxo-dG), a marker of oxidized DNA. Most PV interneuronsexhibit this marker in adult NVHL rats, and the increase in 8-oxo-dGprecedes the loss of PV cell count (O’Donnell et al., 2011).Furthermore, adult NVHL rats show increased cytochrome-oxidase Istaining in the PFC (Tseng et al., 2006), indicating enhancedmitochondrial activity. Thus, several animal models indicate thepossible overlap of interneuron pathology and oxidative stress. Fast-spiking interneurons are highly active and therefore may be morevulnerable to oxidative damage than other cell populations. Interneu-ron oxidative stress may be responsible for the altered behaviorsin NVHL rats, for example, as treatment with the GSH precursorN-acetyl cysteine (NAC) during juvenile and adolescent periodsreverses the loss of PV cell counts and restores deficits in prepulseinhibition of the acoustic startle response (O’Donnell et al., 2011).Animal models not only reveal the presence of oxidative stress ininterneurons, but are providing evidence of a causal role of oxidativestress in abnormal behaviors.A combination of gene variations conferring risk and environmental

factors may thus alter the developmental trajectory of corticalinterneurons. Oxidative stress may be a common final mechanismby which different developmental disturbances may affect cortical PVinterneurons (Fig. 1), and perhaps other cell types as well. Asinterneurons do not mature until late adolescence (Tseng & O’Don-nell, 2007), the deleterious effects of these factors on cortical function(i.e. disinhibited cortical circuits) will not become evident until thetransition to adult stages. If PV interneuron oxidative stress is presentat early stages and even prior to symptom onset, agents that modulateredox balance may be beneficial.

Antioxidants in SZ

Multiple studies have examined the efficacy of drugs with antioxidantproperties on neuropsychiatric disorders. Ginkgo biloba is a potentantioxidant that reduced symptoms when used as an adjuvant (Zhanget al., 2001a,b; Atmaca et al., 2005; Doruk et al., 2008). GSH levelsare reduced in SZ (Do et al., 2000; Gysin et al., 2007; Gawryluket al., 2010), suggesting the possibility that increasing GSH levelsmay be useful in the treatment of SZ. Preclinical studies suggest thatthe GSH precursor NAC may minimize cognitive impairmentsassociated with prenatal exposure to bacterial infections and pro-inflammatory cytokines (Lante et al., 2007). NAC treatment in peoplewith multi-episode schizophrenia improves mismatch negativity(Lavoie et al., 2008) and global psychopathology (Berk et al.,

2008). Finally, a series of studies examined omega 3 fatty acids inpeople with SZ, with mixed results (Fenton et al., 2001; Peet et al.,2001, 2002; Emsley et al., 2006, 2008; Berger et al., 2007). Whenomega 3 fatty acids were used in people who met criteria for high-riskof psychotic disorder, however, they significantly reduced the rate ofconversion to full-blown psychosis (Amminger et al., 2010). This maybe a crucial observation. Antioxidant treatment seems more efficient atearly stages and mostly in ultrahigh-risk subjects. Remarkably, animalmodel data indicate that interneurons exhibit the highest levels ofoxidative stress prior to full symptom onset (O’Donnell et al., 2011).In summary, these studies suggest that antioxidant treatment mayreduce measures of oxidative stress, reduce positive and negativesymptoms, and improve function. However, for this approach to workmost efficiently, treatment at early stages is crucial.

What may come – stem cell-based approaches; genetherapy

If interneuron pathology during development is a critical element inSZ pathophysiology, a major goal should be to restore interneuronfunction as early as possible and even prevent the loss. Besidesreducing oxidative damage, other approaches that may eventuallyameliorate interneuron deficits include stem cell-based replacementand gene therapy. These ideas are still in their early stages, but arelikely to evolve in the next few years. Although one may question thefeasibility of replacing dysfunctional neurons in a tightly intercon-nected population such as PV interneurons, some data suggest it could

NMDA

NMDA hypofunction(noncompeting antagonists)

Reduced afferent inputs (NVHL model)

Loss of trophic factors (BDNF)

Immune activation

Genetic risk factors:DISC1, neuregulin,ErbB4, dysbindin, etc

Oxidative stress

Altered presynaptic modulation(cannabinoids, mGluRs)

Altered postsynaptic modulation(dopamine)

IL-6

other cytokines

Ca++parvalbumin

Hypofunction - loss of parvalbumin

Disinhibited cortical circuits

Fig. 1. Cartoon illustrating a cortical interneuron and a representativeglutamatergic afferent indicating where vulnerability factors can affectinterneuron function during development, and possible events occurring inanimal models that ultimately yield disinhibited cortical circuits. A reduction inNMDA receptor function in GABAergic interneurons could be driven byNMDA antagonists, reduced inputs, reduced trophic factors, etc. ReducedNMDA activation in this cell population induces cytokine expression and redoxalterations, and eventually lower levels of PV. PV is a calcium-bufferingprotein that may not be needed if neurons are hypoactive; therefore, PV lossmay not indicate cell death, but lack of sufficient activity. Genetic risk factorsmay contribute to this scenario both at the pre- and post-synaptic level. BDNF,brain-derived neurotrophic factor. Reproduced from O’Donnell (2011), withpermission.

1868 P. O’Donnell

ª 2012 The Author. European Journal of Neuroscience ª 2012 Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 35, 1866–1870

be possible. Recent evidence suggests that altered neuronal migrationand adult neurogenesis may play a role in SZ. A post-mortem studyrevealed a high number of white matter (WM) neurons in SZ (Funget al., 2011), interpreted as interneuron precursors that failed tomigrate, being stuck in the WM. Another interpretation of such afinding could be that the increased number of WM neurons in SZpatients reflects enhanced neuronal migration in response to a signalfrom a damaged cortical neuronal population. Neurons generated inthe subventricular zone typically travel towards the olfactory bulb viathe rostral migratory stream, even in the human brain (Curtis et al.,2007). Some newly generated neurons have been reported to reach thecortex in primates (Gould et al., 1999). It could be speculated that ifthose neurons were to become interneurons, their role would be toreplenish a neural population that may be vulnerable to a numberinsults, such as fast-spiking interneurons. In that case, a cellreplenishment approach could be feasible by enhancing the rescuemechanism perhaps provided by normal adult neurogenesis.

Conclusion

Restoring excitation–inhibition balance may be critical to addresscognitive deficits in SZ. Several approaches have been attempted inthe past decade. A small trial with an agonist for metabotropicglutamate receptors containing alpha 2 ⁄ 3 subunits (mGluR2 ⁄ 3)showed some promise (Patil et al., 2007), but subsequent trialsshowed an equally high effect of placebo. Other trials with inconclu-sive results included GABA-A agonists (Lewis et al., 2008). Severalstudies addressed the possibility of increasing NMDA receptorefficacy with modulators (Javitt et al., 1994; Heresco-Levy, 2005).Results have been encouraging, but far from conclusive. As GABA–glutamate interactions mature during adolescence (O’Donnell, 2011),it is critical that approaches attempting to restore excitation–inhibitionbalance in SZ are applied at early stages. In addition, antioxidanttreatment may also be effective at early stages, and could even provehelpful to prevent conversion in subjects at high risk for SZ.Regardless of the approach, the field needs to establish biologicalmechanisms that could connect altered immune activation with thedisease and identify proper targets at the optimal time for treatment.This is the time for translational approaches and bold, large-scale,long-term trials with sufficient power to be conclusive.

Abbreviations

8-oxo-dG, 8-oxo-7,8-dihydro-2¢-deoxyguanosine; GABA, gamma-aminobutyr-ic acid; GSH, glutathione; LPS, lipopolysaccharide; NAC, N-acetyl cysteine;NMDA, N-methyl-d-aspartate; NVHL, neonatal ventral hippocampal lesion;PFC, prefrontal cortex; PV, parvalbumin; ROS, reactive oxygen species; SZ,schizophrenia; WM, white matter.

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ª 2012 The Author. European Journal of Neuroscience ª 2012 Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 35, 1866–1870