schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (trycat) pathway,...

Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 5–19

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Progress in Neuro-Psychopharmacology & BiologicalPsychiatry

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Schizophrenia: Linking prenatal infection to cytokines, the tryptophan catabolite(TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopmentand neuroprogression

George Anderson a, Michael Maes b,⁎a CRC, Rm 30, Glasgow, Scotland, United Kingdomb Piyavate Hospital, Bangkok, Thailand

Abbreviations: NMDA, N‐methyl D‐aspartate recnitrosative stress; TRYCAT, tryptophan catabolite; 3-OHKtryptophan 2,3‐dioxygenase; IDO, indoleamine 2,3‐dioxAch, acetylcholine; NE, norepinephrine; nAChr, nicotinicgamma‐amino‐butyric‐acid; APP, amyloid precursor protprotein‐1; FGF1, fibroblast growth factor‐1; NRG-1, neureE; IL, interleukin; PSEN2, presenilin‐2 (PSEN2); TGF, tranquinolinic acid; NO, nitric oxide; SNP, single nucleotideBBB, blood brain barrier; ROS, reactive oxygen species;NAC, N-acetyl cysteine; vit D, vitamin D; BAG-1, bcl‐2 aglucocorticoid receptor; VENs, Von Economo Neurons; CRmone; mGluR, metabotropic glutamate receptors; NAAGCP-II, glutamate carboxypeptidase type II; GSH, glutathi⁎ Corresponding author at: Piyavate Hospital, 998 Ri

10310, Thailand. Tel.: +66 26602728.E-mail address: [email protected] (M. MURL: http://scholar.google.co.th/citations?hl=en&us

(M. Maes).

0278-5846/$ – see front matter © 2012 Elsevier Inc. Alldoi:10.1016/j.pnpbp.2012.06.014

a b s t r a c t
a r t i c l e i n f o
Article history:Received 22 March 2012Received in revised form 6 June 2012Accepted 18 June 2012Available online 16 July 2012

Keywords:CytokinesNeuroprogressionNMDAOxidative and nitrosative stressSchizophreniaTryptophan catabolites

In 1995, the macrophage–T lymphocyte theory of schizophrenia (Smith and Maes, 1995) considered thatactivated immuno‐inflammatory pathways may account for the higher neurodevelopmental pathologylinked with gestational infections through the detrimental effects of activated microglia, oxidative andnitrosative stress (O&NS), cytokine‐induced activation of the tryptophan catabolite (TRYCAT) pathway andconsequent modulation of the N‐methyl D‐aspartate receptor (NMDAr) and glutamate production. The aimof the present paper is to review the current state‐of‐the art regarding the role of the above pathways inschizophrenia. Accumulating data suggest a powerful role for prenatal infection, both viral and microbial, indriving an early developmental etiology to schizophrenia. Models of prenatal rodent infection showmaintainedactivation of immuno‐inflammatory pathways coupled to increased microglia activation. The ensuing activationof immuno‐inflammatory pathways in schizophrenia may activate the TRYCAT pathway, including increasedkynurenic acid (KA) and neurotoxic TRYCATs. Increased KA, via the inhibition of the α7 nicotinic acetylcholinereceptor, lowers gamma‐amino‐butyric‐acid (GABA)ergic post‐synaptic current, contributing to dysregulatedglutamatergic activity. Hypofunctioning of the NMDAr on GABAergic interneurons will contribute toglutamatergic dysregulation. Many susceptibility genes for schizophrenia are predominantly expressed in earlydevelopment and will interact with these early developmental driven changes in the immuno‐inflammatoryand TRYCAT pathways. Maternal infection and subsequent immuno‐inflammatory responses are additionally as-sociated with O&NS, including lowered antioxidants such as glutathione. This will contribute to alterations inneurogenesis andmyelination. In such a scenario a) a genetic or epigenetic potentiation of immuno‐inflammatorypathways may constitute a double hit on their own, stimulating wider immuno‐inflammatory responses andthus potentiating the TRYCAT pathway and subsequent NMDAr dysfunction and neuroprogression; andb) antipsychotic‐induced changes in immuno‐inflammatory, TRYCAT and O&NS pathways would modulate theCNS glia‐neuronal interactions that determine synaptic plasticity as well as myelin generation and maintenance.

© 2012 Elsevier Inc. All rights reserved.

eptor; O&NS, oxidative andY, 3‐hydroxykynurenine; TDO,ygenase; KA, kynurenic acid;acetylcholine receptor; GABA,

ein; BACE1, B‐site APP‐cleavinggulin‐1; Apo-E, apolipoproteinsforming growth factor; QUIN,polymorphism; TH, T helper;

RNS, nitrogen reactive species;ssociated anthanogene‐1; GCr,H, corticotropin‐releasing hor-G, N‐acetylaspartylglutamate;one; NOS, NO synthase.mklongsamsen Road, Bangkok

aes).er=1wzMZ7UAAAAJ&oi=sra

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1. Introduction

Schizophrenia affects approximately 1% of the world's populationand is one of the most severe psychiatric diseases, noted for its chronicand often debilitating processes (Kato et al., 2011). Its etiology, biolog-ical course and treatment still remain elusive. The discovery of the anti-psychotic effects of haloperidol and chlorpromazine in the 1950s,shifted the perspective on schizophrenia to one based on dopamine sys-temdysfunction,with antagonismof the dopamine D2 receptor consid-ered the primary therapeutic target for schizophrenia. Subsequentlyabnormalities in glutamatergic activity have been indicated in the path-ophysiology of schizophrenia. DecreasedN‐methyl D‐aspartate receptor(NMDAr) activity, particularly in the frontal cortex, has been extensive-ly demonstrated (Adell et al., 2012).

A concurrent area of fruitful research has been the study of theimmuno‐inflammatory pathways in schizophrenia. In 1995, Smith

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6 G. Anderson, M. Maes / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 5–19

and Maes (1995) proposed the macrophage–T lymphocyte theory ofschizophrenia suggesting that activated immuno‐inflammatory path-ways are mediators of schizophrenia. This has been largely supportedby later research, with relevance to the neurodevelopmental pathologylinked with gestational infections through the detrimental effects ofactivated microglia, oxidative and nitrosative stress (O&NS), cytokine‐induced activation of the tryptophan catabolite (TRYCAT) pathway andconsequent modulation of the NMDAr and glutamatergic regulation.

Themechanisms of hypo NMDAr activity in schizophrenia overlap toother data showing increased tryptophan 2,3‐dioxygenase (TDO) andindoleamine 2,3‐dioxygenase (IDO) and TRYCAT pathway activation.More specifically an increase in kynurenic acid (KA) inhibits glutamate,acetylcholine (ACh) and norepinephrine (NE) release via the inhibitionof the α7 nicotinic acetylcholine receptor (α7nAChr) (Bencherif et al.,2012). Recent data shows that the α7nAChr also plays a key role in theregulation of different gamma‐amino‐butyric‐acid (GABA)-ergic inter-neurons allowing increased KA to inhibit GABA activity, resulting in a50% loss of GABA-ergic post‐synaptic current, with consequences forpyramidal neuron patterning and co‐ordination (Banerjee et al., 2012).

Neuroimaging studies have shown that schizophrenic patients have asignificant volume reduction of some specific regions in the brainincluding the superior temporal gyrus (STG), an area involved in sensoryprocessing (Menon et al., 1995). This is seen as indicative of an ongoing,if limited, neuroprogressive process, neurodegeneration, neuronal apo-ptosis, and lowered neurogenesis and neuroplasticity. Neuroprogressionis at least partially caused by inflammatory and O&NS pathways (Berk etal., 2011). Degenerative processes are more typically associatedwith thedementias. Interestinglymany of the genes associatedwith the dementiaprocess in Alzheimer's, including amyloid precursor protein (APP), B‐siteAPP‐cleaving protein‐1 (BACE1), fibroblast growth factor‐1 (FGF1),Neuregulin‐1 (NRG‐1), Notch, apolipoprotein E (ApoE)), interleukin‐18(IL‐18), presenilin‐2 (PSEN2) and transforming growth factor‐beta1(TGF‐β1) have been shown to be susceptibility genes in schizophrenia(Akanji et al., 2009; Bradshaw and Porteous, 2012; Jungerius et al.,2008; Liu et al., 2011a; Zaharieva et al., 2008; Zhang et al., 2009).Microg-lia, major sources of various inflammatory cytokines, TRYCAT pathwayproducts, such as quinolinic acid (QUIN), and free radicals such as super-oxide and nitric oxide (NO) in the CNS, play a crucial role in a variety ofneuroprogressive diseases (Kato et al., 2011). Post‐mortem and positronemission computed tomography studies have indicated that activatedmicroglia may be present in schizophrenic patients (Steiner et al.,2008; Takano et al., 2010), with in vitro studies suggesting that antipsy-chotics have anti‐inflammatory effects on microglia activation. The lossof white matter commonly occurs in schizophrenia, and has been pro-posed to explain the etiology and course of schizophrenia (Scheel et al.,in press). Such demyelination has been suggested to be a target for psy-chotropic medication, including antipsychotics (Bartzokis, 2012). Theetiology of schizophrenia is currently thought to result from early devel-opmental processes, especially prenatal viral infection (Brown, 2011).This has led to another avenue of research looking at changes in immunefactors, both in an early developmental context and over the course andtreatment of the disorder.

Here we review the role for changes in systemic immuno‐inflamma-tory pathways, and resultant neuroinflammation in conjunction withchanges in the TRYCAT pathway in co‐ordinating and integrating suchdisparate data and conceptualizations of schizophrenia. This is an areaof active research, with much still to be confirmed by data. As suchthere are gaps, which we have filled with extrapolations from animaldata and directions for future research.

2. Prenatal etiology

2.1. Epidemiological data

An early developmental etiology of schizophrenia has proved anenduring frame of reference. Accumulating data suggest a powerful

role for prenatal infection, both viral and microbial, in driving anearly developmental etiology to schizophrenia (Brown, 2011; Brownand Derkits, 2010), including in animal models (Harvey and Boksa,2012). It has also been suggested that second hits, from other stressorsand trauma, sequentially act to increase disease susceptibility (Read etal., 2001; Vogel et al., 2011). Genetic susceptibilities to trauma, e.g., viavariation in cortisol effects from FK506‐binding protein 51 singlenucleotide polymorphisms (SNP), modulate the consequences oftrauma including depression (Appel et al., 2011), and would thenhave some modulatory effect on first and second hit interactions.

The link between prenatal infection and offspring schizophrenia isnot pathogen‐specific. Different types of viral infections prenatally in-crease the risk of schizophrenia in the offspring (Brown et al., 2004a).Bacterial pathogens likewise increase offspring schizophrenia risk(Babulas et al., 2006). The schizophrenia risk associated with prenatalinfection is increased in offspring with a family history of psychosis,suggestive of a genetic interaction with prenatal infection (Clarke etal., 2009). Epidemiological data shows that 38-46% of schizophreniacases have an association with prenatal infection (Brown andDerkits, 2010), leading to research showing that prenatal infectionproduces specific cognitive and motor deficits in schizophrenia(Brown et al., 2011). Neurological soft signs and cognitive defectsfrequently precede adult-onset schizophrenia and could be markersof a neurodevelopmental process (Leask et al., 2002; van Oel et al.,2002).

2.2. Animal prenatal infection models

Animal models of prenatal infection have been widely developed.Influenza infection of the mother causes a range of changes in theoffspring postnatally, both centrally and peripherally, which areimplicated in the course of schizophrenia (Pacheco-Lopez et al., inpress; Winter et al., 2009). The consequences of prenatal infection in-clude deficits in prepulse inhibition, decreased spatial explorationand social deficits, coupled with increased sensitivity to NMDA‐receptor antagonists and hallucinogens, such as ketamine andphencyclidine. The validity of such behavioral extrapolations fromchanges in rodents to symptoms in schizophrenic patients is a subjectof debate. However, the relevance of prenatal infection to driving be-havioral and structural alterations in the offspring is less controversial.An aspect requiring further investigation is the differential effect thatmay arise from a previously experienced infection (memory infection)versus a naive infection. Almost all published studies have utilizednaive infection. However, only memory infection increases the pro‐inflammatory T helper (TH)17 immune cells, and associated IL‐17cytokine production, in the offspring (Mandal et al., 2010). An enhancedTH17 immune response is associated with autoimmunity and is poten-tiated by IL‐1β and IL‐18 (Lalor et al., 2011). IL‐18 is a susceptibility genefor schizophrenia (Liu et al., 2011a). This could suggest a role for mem-ory versus naive infections in interaction with inflammatory geneticsusceptibilities in conceptualization of schizophrenia as an autoimmunedisorder (Petitto et al., 2012).

Some infectious agents, such as rubella, can penetrate the placentaand have a direct impact on the developing fetus. However, in mostcases the detrimental effects of infection are mediated indirectly viathe induction of the immuno-inflammatory responses in the mother,with consequences for placental and fetal inflammation (Hsiao andPatterson, 2011). Many of these inflammatory changes are mediatedby cytokines, both pro‐inflammatory e.g. IL‐1β, IL‐6, IL‐18, andtumor necrosis factor‐alpha (TNFα) and anti‐inflammatory cytokinese.g. IL‐10, which can regulate both the innate and adaptive immunesystem. Homeostatic processes regulate and limit the inflammatoryresponse, usually preventing any runaway inflammation. The CNS inearly development is particularly sensitive to pro‐inflammatory cyto-kine effects (Tohmi et al., 2007).

7G. Anderson, M. Maes / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 5–19

2.3. Glia and TRYCATs

Microglia and astrocytes in the central nervous system (CNS) arethe main immune type cells regulating inflammatory processes(Reale et al., 2011). Astrocytes co‐ordinate many processes in theCNS, including blood brain barrier (BBB) permeability, neuronalplasticity and activity and microglia activation (Bianchi et al., 2011).As well as having direct impacts on neurons and other cells, cytokinescan also significantly impact on the regulation of tryptophan catabo-lism via TDO (mostly expressed in astrocytes in CNS) and IDO (mostlyexpressed in CNS by microglia). Both TDO and IDO take tryptophanaway from serotonin production and drive it down the kynureninepathways. TDO is a limited pathway leading to the production ofkynurenine and KA, whereas IDO takes tryptophan more fully alongthe kynurenine pathway, leading to the production of neurotoxicand excitotoxic 3‐hydroxykynurenine (3‐OHKY) and quinolinic acid(QUIN). These TRYCATs have significant impact on neuronal activity.Astrocyte KA is an inhibitor of the α7nAChr, resulting in decreasedglutamate, dopamine, ACh, and GABA release (Alexander et al., 2012).At higher than physiological concentrations KA may also decreaseNMDAr activity. QUIN is excitotoxic via the activation of the NMDAr,and is associated with seizures and neuroprogression (Anderson andOjalla, 2010). As such microglia QUIN is associated with excitatoryactivation and over‐activation, whereas KA generally inhibits neuronalactivity, including arousal associated neuromodulatory activity fromdopamine. These different TRYCATs are important in mediating theeffects of different cytokines and stress factors such as cortisol on neuro-nal activity. Cortisol increases TDO andKA, contributing to stress inducedcognitive alterations. TDO is a susceptibility gene for schizophrenia, andthe increase in KA contributes to suboptimal cortex arousal and cogni-tion in schizophrenia (Alexander et al., 2012).

Glia are significant mediators of TRYCAT variations in the CNS.Immuno‐inflammatory processes acting via glia will therefore havean impact on the developmental regulation of GABA, glutamate,ACh, and dopamine. In the course of development different CNSbrain regions develop at varying time points, meaning that changesin the TRYCAT pathways will have differential effects at different pointsin development. For example, a subset of amygdala nuclei maturerelatively early in comparison to other brain areas (Chareyron et al.,2012), suggesting that the effects of stress and maternal infection,driven by cytokines and TRYCATs, will have differential effects at differ-ent time points, in turn altering the amygdala influence on the devel-opment of other CNS regions (Anderson, 2011).

In a recent model of schizophrenia pre‐ and postnatal exposure tokynurenine, viamaternal chowbetween gestational day 15 and postna-tal day 21, leads to a 210% to 341% increase in kynurenine in the brainsof the offspring (Pocivavsek et al., 2012). Increases in kynurenine arestill evident in adulthood and are associated with significant cognitivedeficits. Such data emphasizes the role of peripheral immune inflamma-tion and cytokines in driving changes in peripheral kynurenine withsubsequent impacts on central processing and development.

2.4. Cytokines, neurodevelopment and schizophrenia

Cytokines and their receptors are expressed in the normal fetalbrain, and have a role in normal brain development (Deverman andPatterson, 2009). Different cytokines variably modulate specific neu-ronal subtypes e.g., IL‐1β increases dopamine neuron developmentfrom mesenchymal progenitors (Potter et al., 1999), whereas IL‐6can decrease the survival of serotonin neurons (Jarskog et al., 1997).Also the same cytokine can have opposite effects on neuronal survivalat different developmental time‐points (Doherty, 2007). Therefore, aswell as driving changes in neuronal activity, inflammation‐associatedcytokines can alter the survival and proliferation of specific neuronalsubtypes over development.

Intrauterine infection contributes to many disorders, includingperiventricular leukomalacia, which is driven by increased cytokinesand microglia activation with resultant loss of oligodendrocyteprogenitors (Deng, 2010). However, direct data on the associationof maternal pro‐inflammatory cytokines with offspring schizophreniarisk are relatively limited. Increased maternal IL‐8 (Brown et al.,2004b) or TNFα (Buka et al., 2001) is associated with increased riskof offspring schizophrenia. Animal models better clarify the causalassociations of such factors.

2.5. Animal models of prenatal neuroinflammation

Two animal models of prenatal infection, lipopolysaccharide (LPS)and polyriboinosinic–polyribocytidilic acid (polyI:C), have beenwidely used to look at bacterial and viral effects in pregnancy.Both infections induce increased proinflammatory cytokines, withpolyI:C also inducing the acute phase response to viral infections,including increased IFNα and IFNγ (Traynor et al., 2004; Winter et al.,2009). PolyI:C or LPS administration to the pregnant rodent enhancespro‐inflammatory cytokines in the mother, placenta, amniotic fluid,and fetus. This leads to microglia activation and induction of the pro‐inflammatory transcription factor nuclear factor‐κB in the fetal andneonatal brain (Saadani‐Makki et al., 2008). This is often coupled toõoligodendrocyte precursor cell loss and resultant hypomyelination(Svedin et al., 2005). As such animal models of prenatal infectionprovide clear evidence of increased in‐utero inflammation andneuroinflammation, as well as early links to hypomyelination modelsof schizophrenia.

As a consequence of such neuroinflammation, alterations inbehavioral, cognitive and neurochemical factors occur. Many ofthese have direct links to changes known to occur in schizophrenia,including decreased pre‐pulse inhibition, attention, working memo-ry and sensitivity to antipsychotic medication (Meyer and Feldon,2010; Smith et al., 2012; Yokley et al., 2012). Blocking the actionsof IL‐1β or IL‐6 in the mother prevents the long‐term prenatal LPSand polyI:C effects (Girard et al., 2010; Smith et al., 2007). Thebalance of pro‐and anti‐inflammatory cytokines in also important,as over‐expression of the anti‐inflammatory cytokine IL‐10 preventsthe alterations typically seen after prenatal polyI:C (Meyer et al.,2008a). However, the effects of LPS or polyI:C are systemic, inducingchanges in both the mother and placenta. In order to clarify therole of altered maternal immune responses intramuscular injection ofturpentile oil has been used. This increases maternal immune responsebut with little impact on placental responses. This model shows similarchanges in the offspring to those seen by maternal infection (Aguilar‐Valles and Luheshi, 2011). These results emphasize the importance ofthe maternal response to infection to schizophrenia like changes inthe offspring.

2.6. Maternal infection and structural changes

Maternal infection using polyI:C also results in structural changesin the brains of the offspring, disrupting perinatal cortical laminarformation (Soumiya et al., 2011a). Many of the abnormalities inschizophrenia are layer specific, with most alterations, especially inGABAergic interneurons occurring in Layer V, in the absence of anyindicants of apoptosis, suggesting an early development etiology toLayer V changes in schizophrenia (Charych et al., 2009). Additionally,polyI:C infection induces decrements in fetal neurogenesis (Soumiyaet al., 2011b). Reduced dentate gyrus neurogenesis persists intoadulthood (Wolff et al., 2011). Importantly, this suggests that persis-tent impairments in postnatal neurogenesis and structural changesfollowing prenatal immune challenge are of an early developmentalorigin.

Biological models of schizophrenia have focused on changes in thedopamine system, and the inhibition of the dopamine D2 receptor has


long been thought to mediate the efficacy of typical antipsychotics.Maternal infection with polyI:C has been shown to produce signifi-cant changes in the dopaminergic system, increasing dopamineneurons numbers (Vuillermot et al., 2010), and altering fetal expres-sion of genes involved in dopamine neuron development (Meyer,2013–this issue; Meyer et al., 2008b). Some of these effects are likelyto be driven by cytokine induced changes in TRYCATs. Work byErhardt et al. (2009) show that increased KA, acting to inhibitGABAergic neurons in the ventral tegmental area (VTA), increasesVTA dopamine release. As such this could suggest that prenatal infec-tion, including via pro‐inflammatory cytokines and stress associatedcortisol, acts to increase astrocyte TDOwith resultant increased KAdriv-ing alterations in neuronal activity. This would suggest that not onlystructural changes in dopamine neurons but also altered glia regulationof neuronal activity via TRYCATs drive changes in dopaminergic activity.

2.7. Stress and prenatal infection

It is unclear as to how classical models of stress interact with thechanges associated with prenatal infection. Evidence for a role of in-creased cortisol transfer over, and effects in, the placenta in mediatingmaternal stress effects in the fetus are manifold, linking to decreasedneurogenesis and decreased IQ in the offspring (Coe et al., 2003;LeWinn et al., 2009). Cortisol is a significant regulator of immuno‐inflammatory pathways and cytokine levels and activity, as well asTDO and KA, with subsequent impacts on neuronal activity andinterarea brain communication.

Given the relatively early maturation of some amygdala nuclei(Chareyron et al., 2012), the effects of stress and maternal infectionwill have differential effects in specific CNS regions. Early stress,mediated via cortisol, is known to increase the dendritic complexityof the amygdala, suggesting an early developmental stress influencethat potentiates the amygdala influence on the development ofother brain areas (Anderson, 2011). Accumulating data shows a sig-nificant role for the amygdala in schizophrenia (Pollard et al., 2012),including changes in cortex–amygdala interactions (Anticevic andRepovs, in press; Gee et al., 2012). Amygdala abnormalities are alsoevident in first‐degree relatives of schizophrenic patients (vanBuuren et al., 2011; Wolf et al., 2011). In early development, theamygdala projects into all cortex layers before retracting to leave in-puts into Layers II and V, the two Layers most commonly associatedwith changes in schizophrenia. This suggests that prenatal infectionand stress will interact with the varying development in specificCNS areas at different developmental time‐points to influence bothstructure and interarea co‐ordination. This requires more detailedstudy and may overlap to the effects of chronic unpredictable mildstress (CUMS), which is known to increase QUIN, and thereforeexcitatory activity, in the amygdala and striatum, with a trendincrease in KA in the cortex also being evident (Laugeray et al., 2010,2011). If so, this would suggest direct links of prenatal infection andstress to the differential regulation of the TRYCATs in different CNSareas. As well as suggesting altered GABA, ACh, dopamine and glutamatedifferential regulation in different CNS areas as a consequence of changesin specific TRYCATs. A general increase in TRYCAT activity would drivetryptophan away from serotonin and melatonin production. Alterationsin serotonin and melatonin are evident in schizophrenia (Maldonadoet al., 2009), and in maternally polyI:C infected offspring (Winter et al.,2008).

Prenatal restraint stress has also been shown to induce schizophrenia‐like symptoms in the offspring. Recent data shows that this may beme-diated by significant changes in the epigenetic regulation of GABAergicinterneurons of the prefrontal cortex and hippocampus (Matrisciano etal., in press). As to whether these epigenetic changes are driven bystress/cortisol alterations on amygdala inputs into these brain areasrequires further investigation.

2.8. Other aspects to prenatal infection

2.8.1. Oxidative and nitrosative stress (O&NS) pathwaysSeveral other aspects to maternal infection and maternal and

prenatal cytokines and TRYCATs have been highlighted in differentstudies. Maternal infection and subsequent inflammatory responsesare strongly associated with other pathophysiological effects, includingO&NS, iron deficiency and temporary zinc deficiency (Ganz andNemeth, 2009; Meyer, 2013–this issue; Prasad, 2009). In rodents theproduction of reactive oxygen species (ROS) and reactive nitrogenspecies (RNS) is their predominant defense to innate immune sys-tem activation. This is not the predominant innate immune defense re-sponse in humans,where theproduction of endogenous anti‐microbialsis the more prominent defense. However, oxidant status is relevant inhuman pregnancy, with the enhanced RNS and ROS toxic effects drivingat least part of the detrimental effects of prenatal infection and in-flammation. N-acetylcysteine (NAC), a powerful and ubiquitous anti-oxidant, administration to pregnant mice, protects against prenatalLPS effects on cytokine production and hypomyelination as well as oncognitive and neuroplasticity processes (Lanté et al., 2008). Again thismay be different, if not more relevant, in the rodent response to prena-tal infection than in human response. However, in both humans and ro-dents O&NS pathwayswill play a crucial role in the regulation of cellularplasticity, including immune cell plasticity and response. O&NS path-ways are also a relevant regulator of the TRYCAT pathways, bothdirectly and via the interaction with inflammatory processes. O&NSwill cause damage to lipids, proteins, DNA, and mitochondria (Maeset al., 2011a), with effects being amplified by reduced anti‐oxidantlevels. In pregnancy generally, as well as in schizophrenia, there is astate of enhanced O&NS, which will be amplified by increasedimmuno‐inflammatory responses, contributing to a vicious circle in-volving reduced antioxidants, inflammation, activated O&NS andTRYCAT pathway activation.

2.8.2. Vitamin D, zinc and inflammationIncreased innate immune cytokines IL‐1β and IL‐6 reduce the

availability of iron, as an attempt to starve invading pathogens ofthis essential nutrient. However, iron is also essential for normalbrain development. Inflammation associated decreases in iron couldtherefore interact with prenatal infection (Nemeth et al., 2004). In amodel of maternal turpentine administration the longer term conse-quences are prevented by supplementation with iron (Aguilar‐Valles et al., 2010). Zinc, another essential metal, is also alteredunder pro‐inflammatory conditions. Pro‐inflammatory cytokines in-crease levels of the zinc binding protein metallothionein, peripherallyand centrally, with variations in metallothionein modulating the im-mune response (Pankhurst et al., 2011). In pregnancy zinc deficiencyis detrimental to brain development. As with iron supplementation,zinc supplementation prevents the effects of prenatal LPS infectionon later cognitive changes (Coyle et al., 2009).

It should be noted that deficits in vitamin D (vit D) increase the riskand severity of infection, at least in part via decreasing its induction ofendogenous anti‐microbials, including cathelicidin (Hewison, 2010). Adecrease in vit D will therefore increase the likelihood of infection andof infection severity. Vit D is intimately involved in the regulation of en-dogenous anti‐microbials in humans, but less so in rodents and, as such,is a significant confound in extrapolating from rodent data (Hewison,2010). Decreased maternal vit D is associated with an increased risk ofthe offspring being classed as schizophrenic, and also increases the like-lihood of other known risk factors for schizophrenia, including pre-eclampsia (Anderson, 2010; Byrne et al., 2007). Maternal vit Davailability will have direct impact on the development of the fetalbrain, and via increased bcl‐2 associated anthanogene‐1 (BAG‐1),would be expected to contribute to decreases in cortisol effects at theglucocorticoid receptor (GCr). BAG‐1 prevents the nuclear translocation


of the GCr to the nucleus, therefore inhibiting many of the stress effectsof cortisol on gene transcription.

2.8.3. Gamma–delta T‐cell role?Vit D is also known to have regulatory effects on the activity and

levels of gamma–delta (γδ) T cells (Chen et al., 2005). There is onestudy on γδ T cells in schizophrenia, showing an increase in γδ Tcells in an unmedicated sample (Muller et al., 1998). Recent datasuggests that γδ T cells develop as particular subsets, which predomi-nantly produce IFNγ or IL‐17 (Shibata, 2012). These cells are evidentin the prenatal thymus, and it is unknown as to whether γδ T cellsare relevantly modulated by maternal infection or if variations in vitD would play a role in the modulation of particular subsets. The datashowing that a repeat memory viral infection in pregnancy, but not anaive infection, induces increased TH17 cells and IL‐17 in the offspring(Mandal et al., 2010) may be linked to this. Vit D is known to decreasethe development of TH17 cells (Chang et al., 2010). TH17 cells aregenerally thought to be the major contributors to autoimmunedisorders, including multiple sclerosis, and the regulation of TH17cells and IL‐17 levels by the early developmental influence of γδ Tcells and vit D, may be relevant to conceptualizations of schizophreniaas an autoimmune disorder, as are changes in IL‐2 (Petitto et al.,2012). IL‐18, a susceptibility gene for schizophrenia, induces the expan-sion of IFNγ producingγδ T cells (Li et al., 2009). Notch, another suscep-tibility gene for schizophrenia, is also associated with the regulation ofγδ T cells, where its activation increases IL‐17 producing γδ T cells(Shibata et al., 2011). Gain‐of‐function mutations in the NLRP3inflammasome complex in dendritic cells are associated with enhancedIL‐1β and IL‐18 production and subsequent Th17 responses, and wouldbe expected to modulate immune responses associated with schizo-phrenia, including γδ T cell levels and subsets (Lalor et al., 2011).

2.8.4. Susceptibility genes and developmental inflammationMany of the susceptibility genes for schizophrenia aremost strongly

expressed in early development, suggesting that the processes of prena-tal infection will be interacting with schizophrenia susceptibility genes.In the spirit of Kraepelin and conceptualizations of schizophrenia asdementia praecox (literally: “early dementia”), it is interesting thatmany susceptibility genes for schizophrenia are crucial in the regulationof processes associatedwith Alzheimer's. These susceptibility genes canbe linked to shared processes involving the intercellular interactions ofastrocytes, microglia and neurons, particularly in the regulation ofplasticity. IL‐18 phosphorylates APP and increases BACE1, leading toincreased amyloid B, crucial to conceptualizations of Alzheimer's.IL‐18 also increases neurite outgrowth and synaptic plasticity, likely viaincreased FGF1 (Ojala et al., 2008). FGF1 is very highly expressed inearly development at the time of neuronal growth and connectionformation. FGF1 effects are, at least in part, mediated via the increasedphosphorylation and inhibition of glycogen synthase kinase‐3beta path-way, increasing endogenous anti‐oxidants (Hashimoto et al., 2002).

As part of this beneficial effect, FGF1 induces the activation of liverX receptor (LXR) and the release of ApoE along with high densitylipoprotein cholesterol (HDL) from astrocytes. The ApoE/HDL effluxcontributes to synaptic plasticity, cholesterol for neurosteroid pro-duction, myelin generation and maintenance (Dietschy and Turley,2004), and decreases microglia activity. Notch signaling inhibits thenon‐classical release of FGF1 (Nikopoulos et al., 2007). However,when LPS/IFNγ activates microglia, FGF1 enhances the production ofpro‐inflammatory cytokines TNFα and IL‐6 (Lee et al., 2011a). This sug-gests that variations in microglia activation, increased in schizophreniaand prenatal infection (Bernstein et al., 2009; van Berckel et al., 2008)will have differential inflammatory effects in association with synapticplasticity. It is likely that such activation of microglia would increaseIDO and TRYCATs production, further altering neuronal regulation.The increased KA by astrocytes, evident in schizophrenia, will inhibitthe release and effects of FGF1 (Di Serio et al., 2005), decreasing

ApoE/HDL release and driving changes in neurosteroid production,again evident in schizophrenia (Marx et al., 2011). KA would then beexpected to inhibit synaptic plasticity, but also to inhibit any further ac-tivation of microglia by FGF1. This requires experimental investigation.

The FGF receptor 1 (FGFr1) KO rodent is seen as a model of schizo-phrenia, showing increases in striatal dopamine and decreasedprepulse inhibition (Kucinski et al., 2012), which are reversed bythe application of α7nAChr agonists. This suggests that increases inKA, via the inhibition of the α7nAChr, will significantly regulate thismodel, and FGF1 signaling in schizophrenia. An increase in cAMPsignaling decreases FGF1 synthesis in neurons (Kinukawa et al.,2004), and would simultaneously increase TDO and KA from astrocytes(Luchowska et al., 2009). As such, alterations in neuromodulators suchas dopamine and NE, known to regulate the cAMP pathways, wouldalso impact on FGF1 associated plasticity and neuronal survival, simul-taneously altering astrocyte and microglia TRYCAT activity.

Interestingly, antipsychotics increase ApoE and other LXR genes,suggesting impacts on glia-neuronal interactions (Vik‐Mo et al.,2009). Although increased amyloid B does not seem relevant in schizo-phrenia, it has been suggested that cellular aggregates of DISC1 are im-portant, inhibiting the transport of mitochondria and contributing tometabolic dysregulation (Atkin et al., 2012). Von Economo Neurons(VENs) are reported to show increased levels of DISC1, and are signifi-cantly decreased in early onset schizophrenia (Brune et al., 2010). De-creased VENs levels are associated with frontotemporal dementia, andvia changes in amygdala and anterior cingulate fast communicationlink to changes in empathy and aggression. It is not unlikely that aggre-gation of DISC1 is particularly problematic in VENs, perhaps contribut-ing to the changes in the more chronic course of schizophrenia. Thissuggests another overlap with dementia processes in schizophrenia. Itis unknown as to whether immune and TRYCAT pathways wouldhave a role in the regulation of such DISC1 aggregates or VEN density.Variations in DISC1 also interact with prenatal infection to enhanceschizophrenia‐like changes in the offspring (Ibi et al., 2011). Interest-ingly, prenatal infection at later time-points in rodents, increases theproduction of amyloid B, accelerating the neurodegenerative processin an Alzheimer's model (Krstic et al., in press). This suggests furtheroverlaps of schizophrenia and Alzheimer's driven by prenatal infection,with priming for these twodisorders perhaps beingdifferentiated by in-fection at different time-points in pregnancy.

3. Long‐term consequences of prenatal infection

3.1. Immuno‐inflammatory pathways

A recent meta‐analysis shows significant changes in immuno‐inflammatory measures in adult presentations of schizophrenia(Miller et al., 2011). A wide range of data in schizophrenic patientsshows changes in TH1 and TH2 type cytokine levels, low grade inflam-mation (Potvin et al., 2008) and indicants of microglia and astrocyteactivation (Bernstein et al., 2009; van Berckel et al., 2008). How aresuch changes linked to the above early developmental etiology?Maintained alterations in peripheral pro‐inflammatory cytokinescoupled to increased glia activation, are evident in different models ofprenatal rodent infection, including influenza (Fatemi et al., 2004),LPS (Romero et al., 2010), prenatal IL‐6 (Samuelsson et al., 2006), andpolyI:C infections (Juckel et al., 2011). This has led to the suggestionthat prenatal infection primes the organism for an altered inflammatoryresponse to later inflammatory activators, the latter acting as a secondhit (Meyer, 2013–this issue). This second hit may take the form of ge-netic mutations e.g. in IL‐18, or the form of stress or more direct im-mune activators (Liu et al., 2011a). Prenatal “memory” infection, andthe induction of TH17 responses, being an example of such early prim-ing with later immune consequences (Mandal et al., 2010).

Studies over the rodent lifespan following prenatal immune infec-tion suggest that the prenatal inflammation‐induced changes are


progressive, being manifest only in adolescence or later (Meyer et al.,2008c; Vuillermot et al., 2010). This would seem to parallel the emer-gence of symptoms in schizophrenia, suggesting that prenatal inflam-mation is not a static change, but interacts with stressors over thecourse of development, with resultant progressive changes in the na-ture of the immune and inflammatory response. Such sensitizing effectsmay occur both centrally and peripherally e.g. polyI:C infection in-creases microglia activation in adolescence (Juckel et al., 2011) and pe-ripheral TNFα increases precede prepulse inhibition deficits followingprenatal LPS (Romero et al., 2010). It is likely that the TRYCAT pathwaywill be concurrently altered, increasing the kynurenine/tryptophanratio as has been shown in schizophrenia (Lee et al., 2011b). Giventhat over 60% of brain kynurenine is peripherally derived (Galand Sherman, 1980), this may be relevant as to how changes in periph-eral inflammation impact on central processes over the course ofdevelopment.

The immuno‐inflammatory changes occurring in schizophreniashow a number of mixed results across studies. In a meta‐analysisof immune marker changes in first episode and acutely relapsedschizophrenic patients Miller et al. (2011) suggest that IL‐1, IL‐6and TGF‐β1 are state markers, given their increase in both acuteand first episode patients and their subsequent normalization byantipsychotics. In contrast, IL‐12, IFNγ, TNFα and sIL‐2r are proposedas trait markers, as their elevated levels in acute exacerbations weremaintained following antipsychotic treatment.

Acute relapse is common and often associated with adverse out-comes, including increased treatment‐resistant symptoms, cognitivedecline, and functional disability (Wyatt, 1991; Miller et al., 2011).This highlights the importance of a better understanding of alter-ations in immune and inflammatory responses. Although strict inclu-sion criteria for this meta‐analysis were set, most studies did notcontrol for potential confounding factors such as body mass indexand smoking (Miller et al., 2011). As such potential immunologicalconfounds will arise, given that metabolic syndrome is known tohave pro‐inflammatory consequences, as well as being modulatedby unmeasured dietary factors (Jin et al., 2007).

IL‐18 and IL‐28 are two susceptibility genes for schizophrenia(Chen et al., 2012; Liu et al., 2011a). IL‐18 is increased in schizo-phrenia, and is downregulated by antipsychotics (Reale et al., 2011).IL‐18 may show co‐ordinated release with IL‐1β via their mutualinduction by caspase‐1 and inflammasome activation (van deVeerdonk et al., 2011). IL‐18 is a powerful inducer of IFNγ, which inturn, is the major TH1 cytokine and the most powerful regulator ofIDO and the TRYCAT pathway. As such changes in the inflammasomeand IL‐18, centrally and peripherally, may be significant modulatorsof patterned immune and cytokine responses as well as regulatingthe levels of IDO and TRYCATs. IL‐28 is probably more relevant in anearly developmental context, given its powerful role in the regulationof response to viral infection (Osaki et al., 2012). How relevant ismaternal IL‐28 genetic SNPs to the regulation of consequences for thefetus following maternal viral infection? Would IL‐28 SNPs in thefetus also be relevant, including in the modulation of the course andmanagement of adult manifestations of schizophrenia? Future researchwill hopefully provide some answers to these questions.

3.2. Immuno‐inflammatory theories

A number of hypotheses have been postulated to explain theimmune‐cytokine basis for schizophrenia. Smith and Maes (1995) putforward the macrophage–T‐lymphocyte theory postulating that IL‐1,IL‐2, TNFα and IFNγ produced by chronically activated macrophagesand T‐lymphocytes are the fundamental mediators of schizophrenia(Miller et al., 2011). The recent meta‐analysis by Miller et al. (2011)generally supports the macrophage–T‐lymphocyte theory (Maes et al.,1995, 1996, 1997, 2000). However, there was a nonsignificant decrease

in IL‐2, although this may be due to increased binding of IL‐2 by sIL‐2R,which was increased in first episode patients.

Schwarz et al. (2001) suggested that a shift away from TH1‐cellimmune function towards TH2‐cell immune responses predominatesin schizophrenia. The Miller et al. (2011) meta‐analysis provided lessconsistent evidence in favor of the TH2‐hypothesis. Increased IFNγand sIL‐2R support a TH1 response in acute exacerbations, supportedby other data showing increased neopterin and KA. Also, there was asignificant decrease in the TH2 cytokine IL‐10 in acutely relapsedpatients. Similarly an earlier systematic review found no evidence tosupport a bias to a TH2 response in schizophrenia (Potvin et al.,2008).

Recent data suggest that a mixed TH1/TH2 response may actuallyoccur, with increases in both TH1 and TH2 responses (Drexhage et al.,2011). In support of this,Miller et al. (2011) found evidence for activationof the compensatory anti‐inflammatory response syndrome, a counter‐regulatory mechanism that inhibits the primary inflammatory responseand involves an adaptive reprogramming of leukocytes (Adib‐Conquyand Cavaillon, 2009) in schizophrenia, including increased IL‐1RA andTGF‐β in acute exacerbations that decreased with antipsychotic treat-ment. Earlier data also shows an increase in TH1 and TH2 cytokines, in-cluding IFNγ and IL‐4 (Avgustin et al., 2005). The Miller meta‐analysisshows no consistent association of measured inflammatory markersand clinical features, including positive and negative symptoms (Milleret al., 2011). To some degree the relatively small range of inflammatoryfactors open for inclusion in the meta‐analysis may underlie this lack ofclinical association.

Monji et al. (2009, 2013–this issue) ascribed a key role to activatedmicroglia release of proinflammatory cytokines and ROS in drivingabnormal neurogenesis, neuronal degradation, and white matterabnormalities in schizophrenia. Data showing the effects of antipsy-chotics on microglia activity provide indirect support of this theory(Monji et al., 2013–this issue). It should be noted that changes in mi-croglia activation can be viewed as an integral part of wider peripher-al immune changes, with alterations in the TRYCATs peripherallycontributing to glia activation. The finding of a general increase in IL‐1in the Miller et al. (2011) meta‐analysis is consistent with this.

3.3. Activation of the TRYCATs pathway

Increased TRYCAT levels in the frontal cortex in schizophrenia haveclassically been linked to cognitive deficits (Muller et al., 2011). Morerecent data shows wider changes in TRYCAT pathways. A study byMyint et al. (2011) in medication free schizophrenic patients, showeddecreased plasma levels of KA, and increased 3‐OHKY with increasedkynurenine/KA (KY/KA) and 3‐OHKY/KA ratios at presentation.Similarly Condray et al. (2011) showed increased 3‐OHKY levelsin schizophrenic patients at first presentation, with the level of 3‐OHKY predicting symptom improvement. 3‐OHKY is neurotoxic to neu-rons. However, a decrease in kynurenine 3‐monooxygenase, whichconverts kynurenine to 3‐OHKY, is evident in the frontal eye fieldsand Brodmann areas 9 and 10 in schizophrenia, suggesting local regu-lation of the TRYCAT pathways (Sathyasaikumar et al., 2011; Wonodiet al., 2011).

An increase in peripheral kynurenine, generated by increased IFNγ,IL‐18, IL‐1α and TNFα, will induce IDO activity; whereas stress associ-ated cortisol will increase TDO in astrocytes. Increased peripheralkynurenine readily crosses the BBB, andwill be converted by astrocytesto KA, contributing to decreases in cognition and to the inhibition ofthe α7nAChr, in turn altering glutamate, GABA, dopamine and ACh.As such the genetic SNPs in IL‐18, TNFα (Boin et al., 2001) and themu-opioid receptor, via cAMP regulation of TDO (Luchowska et al.,2009), will also have direct impacts on the regulation of TRYCATpathway modulation of neurotransmitter releases. In such a scenarioa genetic or epigenetic potentiation of such inflammatory cytokines


would differentially modulate neuronal activity, at least in part via thepotentiation of kynurenine production, including peripherally.

If the stressful nature of such a debilitating disorder parallels theeffects of CUMS in increasing QUIN in the amygdala and striatum,then differential activation and atrophy in these brain regions wouldcontribute to the altered patterning and inter‐area connectivity oftenfound in schizophrenia and those at high risk (Gee et al., 2012). Sucha scenario allows the early developmentally influenced alterations inperipheral immune responses to generate alterations in behavior, cog-nition and affective processing, in interaction with genetic susceptibili-ties, and ongoing stressors/trauma. This would link to the data showingthat schizophrenia patients often report periods of stress around thetime of transition to symptom exacerbation (Phillips et al., 2006).

As well as the differential regulation of the TRYCATs, CUMS inrodents increases IL‐1β, IL‐6 and TNFα in the CNS, decreasingTGF‐β1, IL‐10, and neurogenesis (You et al., 2011). It is unknown asto whether such cytokine production in the CNS is area specific oras to whether there is an association with variations in levels ofcorticotropin‐releasing hormone (CRH), which is known to locally in-duce IL‐1β in astrocytes and IL‐18 in microglia (Yang et al., 2005).Systemic IL‐1β is also known to increase CRH in specific CNS regions(Brunton and Russell, 2008). This could suggest that local CRH, viaincreased astrocyte IL‐1β or mast cell activation (Esposito et al.,2002), could increase BBB permeability. Physical or psychologicalstressors are known to activate microglia, enhancing pro‐inflammatorycytokines in the CNS (Garcia‐Bueno et al., 2008).

Other models of schizophrenia‐like symptoms, e.g. social isolation,may also act as a second hit to prenatal infection, as it does at latertime points (Gandhi et al., 2007). Recent data shows that socialisolation for 8 weeks significantly impacts on the TRYCAT pathways,increasing plasma kynurenine, QUIN and anthranillic acid, whilst KAwas significantly decreased (Moller et al., 2012). Clozapine reversedall these changes. Interestingly the administration of kynurenine torodents in adolescence, but not in adulthood, impairs social behavior(Trecartin and Bucci, 2011). This suggests that the immune and cyto-kine induced changes in the TRYCAT pathways that drive alterationsin neuronal activity to prenatal infection may also be significant medi-ators of the second hit protocols, including social isolation and CUMS.

4. Glutamate and hypoNMDAr models

4.1. HypoNMDAr

Initial conceptualizations of the role of the NMDAr in schizophreniaposited a general decrease in overall glutamatergic tone in the brain,leading to a global deficit in glutamatergic activity (Kim et al., 1980).Measurements did not confirm this (Javitt and Zukin, 1991), suggestingthat a more complex dysregulation in glutamatergic function may beinvolved. More recently it has been shown that hyper, rather thanhypo, glutamatergic activity is evident in schizophrenia (Moghaddam,2003). The core tenet of current conceptualizations is that schizo-phrenia is associated with hypofunction of the NMDAr, leading tohypostimulation of GABA inhibitory interneurons and disinhibitedglutamate release. Contributing to the glutamatergic hypothesis ofschizophrenia is the observation that administration of non‐competitiveNMDAr antagonists, such as phencyclidine and ketamine, can inducebehavioral and neuropsychological effects in healthy volunteers thatresemble schizophrenia, and can profoundly exacerbate psychotic symp-toms in schizophrenic patients (Krystal et al., 2003).

An increase in astrocyte KA could be expected to directly inhibit theNMDAr, and therefore parallel some of the effects of phencyclidine andketamine. However, the physiological concentration of KA in the CNS isnot high enough to achieve this. Rather it seems that KA has its effectsvia the inhibition of the α7nAChr on GABAergic interneurons, decreas-ing GABA release by about 50% (Banerjee et al., 2012). The inflammato-ry regulation of the TRYCAT pathway, including via increased peripheral

kynurenine, coupled to the effects of increased cortisol, would thencontribute to increased KA production and GABAergic interneuroninhibition. KAmay also decrease presynaptic glutamate release, howeverthe balance of its effects in schizophrenia would seem to be for height-ened glutamate release. Perhaps more importantly the effects of KAwould change the role of GABA-ergic networks in the regulation, andsynchronization, of pyramidal neuronal activity (Banerjee et al., 2012).

Dysregulated glutamate release does not seem evident in all brainregions in schizophrenia, and it is unclear as to why relativelyrestricted dysregulation should occur. The data by Laugeray et al.(2010) showing increased KA in the cortex and increased QUIN inthe amygdala and striatum could suggest that chronic low level stresssignificantly, and differentially, regulates the specific TRYCATs pro-duced in particular CNS regions, driving differential glutamatedysregulation. Variations in levels of microglia activation may be rel-evant to this, especially since activated microglia are another sourceof glutamate release. Variations in the BBB permeability and uptakeof peripheral kynurenine could be another factor that modulates var-iations in KA level, α7nAChr activation, hypoGABA-ergic activity andhyperglutamate release, as is variable expression of the α7nAChr onGABAergic interneuron subtypes.

4.2. HypoNMDAr and metabotropic glutamate receptors

Another aspect of the glutamate hypothesis is decreased activationof the presynaptic metabotropic glutamate receptors 2/3 (mGluR2/3),which acts to inhibit glutamate release in conditions of overspill fromthe synapse (Moghaddam and Javitt, 2012). This is currently a treat-ment target in schizophrenia (Patil et al., 2007). Astrocytes play asignificant part in the dysregulation of glutamatergic activity. Giventheir wider glutamatergic regulation via glutamate uptake trans-porters, N‐acetylaspartylglutamate (NAAG) and glutamate carboxy-peptidase type II (GCP‐II) expression, astrocytes are key cells incoordinating changes in glutamate regulation. NAAG levels are alteredin schizophrenia (Jessen et al., in press). GCP‐II cleaves and inactivatesNAAG, an agonist at the mGlur3. A GCP‐II inhibitor, via the potentiationof endogenous NAAG at mGluR3, reduced the schizophrenia‐likesymptoms in rodents (Olszewski et al., 2008), including reducedhyperactivity, stereotypies and a behavioral homolog of negative symp-toms produced by treatment with the potent NMDAr antagonist,dizocilpine (Patil et al., 2007). An orally active GCP‐II inhibitor,2‐PMPA, attenuates dizocilpine‐induced prepulse inhibition deficits inmice (Takatsu et al., 2011). The regulation of astrocytes by immune as-sociated inflammatory factors would seem crucial to this widerglutamatergic regulation and co‐ordination.

The TRYCAT pathways may also have a role in the modulation ofmGluR3. Xanthurenic acid (XA), a molecule arising from tryptophanmetabolism by transamination of 3‐OHK, has recently been identifiedas an endogenous mGluR2/3 ligand in vitro and in vivo (Copeland etal., in press). This suggests that variations in the TRYCAT pathways,evident in schizophrenia, will significantly modulate the wideraspects of glutamatergic signaling, including mGluR3 activity.

4.3. HypoNMDAr and anti‐oxidants

Astrocytes can efflux glutamate by at least three routes: via thecysteine–glutamate antiporter (Cys–GluX); via vesicular release;and via connexin‐43 hemichannels (Hertz, 2012). Synaptic activationof the NMDAr induces NO release to astrocytes leading to increasedastrocyte glutathione (GSH) synthesis and export, in turn drivingincreases in the activation of the Cys–GluX, leading to glutamate effluxin exchange for cysteine uptake (Gegg et al., 2003). There is increasingevidence that GSH metabolism is abnormal in schizophrenia and thata weakened capacity to synthesize GSH under oxidative stress is asusceptibility factor for schizophrenia (Bókkon and Antal, 2011;Boškovic et al., 2011). Patients with schizophrenia show a deficit in


GSH levels in the prefrontal cortex and cerebrospinal fluid, as well as areduction of gene expression of GSH‐synthesizing enzymes (Do et al.,2000; Gysin et al., 2007). GSH plays a major role in modulating redox‐sensitive sites, including NMDA receptors (Choi and Lipton, 2000). Inthe rat hippocampus, reduced GSH levels weaken NMDA‐mediated re-sponses and synaptic plasticity (Bókkon and Antal, 2011; Steullet et al.,2006). Cabungcal et al. (2006) provides experimental evidence that aGSH deficit induces dysfunctions in GABAergic neurons in the anteriorcingulate cortex of rats, an important area for GABA dysregulation inschizophrenia (Pierri et al., 1999). GSH knockdown alters glucose me-tabolism and glycogen utilization in astrocytes, changing a fundamentalaspect of brain energy metabolism, with relevance to wider metabolicdysfunctions observed in schizophrenia (Lavoie et al., 2011). GSH and ox-idant status are also important regulators of the TRYCAT pathways (Maeset al., 2011a, 2011b), suggesting that some of the impact of decreasedanti‐oxidant status will be mediated via altered TRYCAT pathwayregulation.

4.4. HypoNMDAr and NO

In addition recent data provides solid evidence that nitric oxidesynthase 1 (NOS1) is associated with schizophrenia (Cui et al.,2010; Reif et al., 2006, 2011). The risk allele of NOS1, rs41279104,results in about a 30–50% decrease of exon 1c expression (Cui et al.,2010). As exon 1c is the predominant isoform in the frontal cortex,this will either result in decreased total NOS1 expression or in achange in alternative first exon expression patterns (Reif et al.,2011). As Cui et al. (2010) assessed total NOS protein levels, andfound that the amount of NOS1 protein is reduced by 50% in risk allelecarriers, a decrease in total NOS1 expression seems to take place. Theresultant compromised prefrontal NO signaling, and associated alter-ations in GSH production and redox regulation of the TRYCAT, willdysregulate the crucial intercellular signaling between neurons andglia, contributing to cognitive deficits in schizophrenia. NOS is pre-dominantly expressed in GABA-ergic interneurons of the prefrontalcortex, and is known to inhibit GABA-ergic activity (Reif et al.,2006). NOS1 alteration in schizophrenia will therefore contribute tothe dysregulation of glutamatergic activity. Some data suggests in-creased NO and NO metabolites in the periphery and brain in schizo-phrenia (Taneli et al., 2004; Yao et al., 2004), although the specificcellular source requires further research.

4.5. HypoNMDAr and microRNAs

Recent data suggests a role for microRNAs (miRNAs) in co‐ordinating the changes driven by hypoNMDAr activity (Miller et al.,2012). miRNAs are small noncoding RNA sequences crucial to the reg-ulator of developmental and adult processes by coordinating the ac-tivity of multiple genes within biological networks. Miller et al.(2012) looked at 854 miRNAs in the prefrontal cortex of 100 control,schizophrenic, and bipolar subjects. The cyclic AMP‐responsive ele-ment binding-protein and NMDA‐regulated microRNA miR‐132 wassignificantly decreased in two independent schizophrenia cohorts. Ofthe miR‐132 target genes, 26 were increased in the schizophrenic sam-ple in schizophrenia subjects. Consistent with hypo‐NMDAr function,pharmacological inhibition of the NMDAr in adult mice results inmiR‐132 down‐regulation in the prefrontal cortex. Mouse miR-132expression is developmentally regulated, overlapping with criticalneurodevelopmental processes during adolescence (Miller et al.,2012). The data suggest that miR‐132 dysregulation and subsequentabnormal expression of miR‐132 target genes contribute to theneurodevelopmental and neuromorphological pathologies present inschizophrenia. As such the role of miR‐132 in co‐ordinating gene net-works would be downstream of inflammation and TRYCAT pathway in-duced changes in NMDAr function.

5. Neuroprogression and schizophrenia

Schizophrenia has long been associated with neuronal loss, goingback to the original conceptualization of dementia praecox. A morerecent trend has been to look for restricted levels of neuronal degen-eration, much of which has focussed on the temporal lobe, especiallythe superior temporal gyrus (STG) (Menon et al., 1995). It has beensuggested that enhanced dopamine D2 receptor activation of sensoryinputs from the STG to the lateral amygdala, the site of fear memorystorage, results in an amygdala negative feedback to the STG thatmay contribute to STG atrophy (Anderson, 2011). Moreover, wideratrophy has been shown to occur prodromal to, or during, majorsymptom exacerbation in schizophrenia (Hulshoff Pol and Kahn,2008; Wood et al., 2008). It is still unclear as to whether this is a pro-cess of neuroprogression, if only intermittent. As highlighted abovethe increased levels of glutamate in schizophrenia, including inhigh‐risk and first episode patients (de la Fuente‐Sandoval et al.,2011), may contribute to neuroprogression. Activated microgliawould also contribute to increased glutamate as well the neurotoxicQUIN and 3‐OHKY (Muller et al., 2011; Wonodi and Schwarcz,2010). Any increase in QUIN, 3‐OHKY and glutamate would undoubt-edly contribute to neuronal loss. This would also give an upstreamrole to immune activation, inflammation and TRYCAT pathwayinduction.

Degenerative processes are the cornerstone of the pathologydriving the dementias. Many of the genes that are risk factors, orhave protein levels increased in Alzheimer's, including BACE1, FGF1,NRG‐1, Notch, ApoE, IL‐18 and TGF‐B1 have been shown to be suscep-tibility genes in schizophrenia (Xu et al., 2006), and as highlightedabove will have a crucial role in the early developmental etiology ofschizophrenia, including via altered synaptic plasticity. These same sus-ceptibility genes would be expected to contribute to processes drivingneuronal loss over the course of neuroprogression in schizophrenia.Again changes in levels of immune activation, cytokine productionand TRYCAT pathway activity would intimately interact with theeffects of such susceptibility genes.

6. Treatment implications

6.1. Antipsychotics and cytokines

Many antipsychotic drugs are known to exert inhibitory effects onimmuno‐inflammatory pathways including on pro‐inflammatorycytokine production (Drzyzga et al., 2006). In the Miller et al.(2011) meta‐analysis blood levels were measured at baseline andafter a mean of 53 days of antipsychotic treatment in 488 patients fol-lowing an acute exacerbation of psychosis. Antipsychotic medicationwas not standardized in 58% of studies. Antipsychotics significantlyincreased sIL‐2R and IL‐12 and decreased IL‐1β, IL‐6 and TGF‐β. Theadministration of IL‐12 to cancer patients increases sIL‐2R, neopterinand TNFα (Lissoni et al., 1998).

In the two studies that reported a significant positive correlationbetween IL‐6 levels and total psychopathology scores at baseline(Frommberger et al., 1997; Pae et al., 2006), there was also a significantpositive correlation between the change in IL‐6 levels and change intotal psychopathology scores with anti‐psychotic treatment (Miller etal., 2011). However, as well as heterogeneity in the nature of schizo-phrenia, there is also some heterogeneity in terms of antipsychotic ef-fects on the immune system e.g. clozapine has been shown to increasesIL‐2R and IL‐6 levels (Maes et al., 1994), whereas quetiapine also in-creases sIL‐2R, but has no effect on IL‐6 or IL‐1RA (Igue et al., 2011).This study also showed that quetiapine enhancement of sIL‐2R was as-sociated with reduced positive symptoms.

Antipsychotic induced changes in cytokines occurred within weeksof treatment in patients with an acute exacerbation of psychosis. Onestudy found significant changes in cytokine levels after a mean of


4 weeks of antipsychotic treatment (Song et al., 2009). Another studyshowed that IL‐6 decreased within 9 days of antipsychotic treatmentfollowing an acute relapse, and by 8 weeks there was no significant dif-ference between patients and control subjects (Frommberger et al.,1997). Either clozapine or risperidone decreased raised levels of IL‐2,IL‐6, IL‐18 and TNFα after 6 months of treatment (Lü et al., 2004).Risperidone, but not haloperidol, regulates cytokine production bydendritic cells, the main antigen presenting cells (Chen et al., 2012),increasing IL‐10, IL‐6, IL‐8 and TNFα, but decreasing IFNγ‐inducibleprotein‐10 and IL‐12 as well as lowering IFNγ production by T‐cells.Taken together, these findings suggest that cytokine alterations maynormalize to some extent shortly after treatment for an acute exacer-bation of psychosis (Miller et al., 2011). However, antipsychotics mayalso have indirect effects on the functioning of specific CNS areas,which in turn regulate brain immune responses. Haloperidol increasesnerve growth factor in the CSF (Fiore et al., 2008), which can be takenup by tanycytes and specifically transported to the locus coeruleus,modulating NE production (Feng et al., 2011). NE is classically associat-ed with immune regulation.

6.2. Antipsychotics and treatment resistance

A meta‐analysis cautiously suggests that sIL‐2R levels may be amarker for patients with treatment‐resistant psychosis (Miller et al.,2011). A longitudinal treatment study in continuously ill patientsalso showed an increase in sIL‐2R (Bresee and Rapaport, 2009). Treat-ment resistance is also associated with decreased plasma tryptophan,which correlated with increased cortisol (Lee et al., 2011b). This couldsuggest that treatment resistance is linked to increased activation ofthe TRYCAT pathway. Cortisol has been shown to be correlated withIL‐18 levels in some human conditions, suggesting that increased IL‐18, and subsequent induction of IFNγ and IDO, may be preferentiallyassociated with treatment resistance.

6.3. Antipsychotics and TRYCATs

Antipsychotics have direct and indirect effects on microglia activa-tion (Kato et al., 2008; Monji et al., 2013–this issue). Hence, antipsy-chotics will dampen on‐going inflammatory processes both centrallyand peripherally. In line with the idea of immune mediated inflamma-tory responses driving changes in neuronal activity in part via the reg-ulation of glia TRYCATs, recent data shows significant impacts ofantipsychotics on the levels of different TRYCATs, includingkynurenine, KA and 3‐OHKY (Myint et al., 2011). This study showeddecreased levels of plasma KA, and increased 3‐OHKY with increasedKY/KA and 3‐OHKY/KA ratios at presentation inmedication free schizo-phrenic patients. After 6 weeks treatment KA levels increased and 3‐OHKY levels decreased, significantly increasing the KA/3‐OHKY ratio.Higher plasma KA or decreased KY/KA ratio at admission correlatedwith reduced clinical symptoms at discharge although decreased KY/KA at admission was associated with positive symptoms score, with in-creased 3‐OHKY correlating with lower positive symptoms score. It islikely that increased 3‐OHKY would be associated with increasedQUIN, although this could depend on the expression of other TRYCATpathway regulators. These results indicate that there is an imbalancein the TRYCAT pathway in schizophrenia, with temporal overlaps tochanges in immune parameters induced by antipsychotics. This issupported by the findings of Condray et al. (2011) who showed that in-creased 3-OHKY associated with lower changes in clinical symptomsfollowing 28 days of treatment in a sample consisting of schizophrenicpatients who were either medication-naïve or currently medication-free.This parallels the data showing that relatively attenuated increases in IL‐2 and IL‐8 at baseline are correlated with enhanced symptom improve-ment (Zhang et al., 2004). These results add credence to the role of im-mune associated inflammatory responses driving change in TRYCATs,with subsequent impacts on neuronal regulation. That over 60% of

brain kynurenine is peripherally derived gives further credence to thismodel (Gal and Sherman, 1980).

6.4. Antipsychotics and myelination

Alterations in myelin and oligodendrocyte abnormalities aresuggested to play an important role in the etiology of schizophrenia(Garver et al., 2008). ApoE release with cholesterol is essential to thegeneration and maintenance of myelin (Dietschy and Turley, 2004).Deficits in astrocyte ApoE/HDL cholesterol reduce synapse formationand dendrite maturation in cultured neuronal cells (Goritz et al.,2002). Polymorphisms in the sterol‐responsive element‐bindingproteins are associated with schizophrenia, suggesting that variationin lipid biosynthesis affects disease susceptibility (Le Hellard et al.,2010). Changes in ApoE levels in the CNS and periphery have previouslybeen reported in patients with schizophrenia (Dean et al., 2008).Antipsychotic induced activation of ApoE reported by Vik-Mo et al.(2009) suggests treatment efficacy via increased ApoE/HDL cholesteroldriving changes in synaptic plasticity and myelination, with significantinteraction of other schizophrenia susceptibility genes, such as FGF1and DISC1, in these plasticity and myelination regulating pathways(see Section 2.8.4). The attenuated activity of the TRYCAT pathwaysand inflammatory responses by antipsychotics would then modulatethe KA inhibition of FGF1 induced LXR, and subsequent ApoE and HDLcholesterol production. In such a scenario antipsychotic inducedchanges in immuno‐inflammatory and TRYCAT pathway activitieswould modulate the CNS glia‐neuronal interactions that determinesynaptic plasticity as well as myelin generation and maintenance. Ithas been shown that antipsychotic induced weight gain and increasedserum lipids correlate positively to treatment response (Bai et al.,2006; Procyshyn et al., 2007). The altered regulation of cholesterolwould suggest reasons for these side‐effect associations with the clini-cal efficacy of antipsychotics.

In the context of overlaps with Alzheimer's associated pathways,BACE1 is crucial to the cleavage of NRG‐1, including in early develop-ment, suggesting links of these pathways to the hypomyelinationfound in schizophrenia (Fleck et al., 2012). NRG‐1 plays a crucial rolein the regulation of myelination. The BACE1 KO rodent has been pro-posed as a model of schizophrenia (Savonenko et al., 2008). However,a direct link to decreased BACE1 in the cortex in schizophrenia has notbeen found (Dean et al., 2008). It remains to be determined if the alter-ations in immune cells and glia in schizophrenia contribute to differentialregulation ofwider intercellular interactions, of which BACE1 andNRG‐1are a part.

6.5. Adjunctive treatments

6.5.1. PregnenoloneRecently proposed treatments for schizophrenia include pregneno-

lone, which is known to increase myelination, as well as modulatingNMDAr and GABA type A receptor (GABAAr) activation, the latter effectbeing via the metabolite allopregnenolone (Marx et al., 2011). Alter-ations in neurosteroid production are evident in schizophrenia, andare increased by antipsychotics. Again the upstream factors mediatingsuch inhibition of neurosteroid production will include the immuno‐inflammatory associated regulation of the TRYCATs, especially giventhe role of KA in the inhibition of FGF1 induced LXR, ApoE and HDLcholesterol, altering the availability of cholesterol for neurosteroidsynthesis.

6.5.2. D‐SerineD‐Serine is sometimes used in the treatment of refractory schizo-

phrenia, with its efficacy mediated by increased activation of theNMDAr. However, a single injection of D‐serine increases IL‐2, IL‐3,IL‐5, IL‐6 and TNFα, suggesting that some of its early effects couldbe mediated via changes in immuno‐inflammatory responses


(Davidson et al., 2009). As to whether longer‐term treatment with D‐

serine has immune consequences requires further investigation.Interestingly clozapine, but not haloperidol, increases the release ofD‐serine from astrocytes (Tanahashi et al., 2012).

6.5.3. MelatoninThe decreased levels of melatonin in schizophrenia, and the effects

of olanzapine to decrease melatonin by 55% in rodents (Raskind et al.,2007) should not be underestimated regarding the influence of mel-atonin on immune function. Considerable research shows melatoninas an anti‐inflammatory agent. However, the immune–pineal axis isan important regulator of the balance and circadian rhythm ofimmune functioning (Pontes et al., 2007; Srinivasan et al., 2008).The switch between central and local production of melatonin shouldhave a temporal profile according to the passage between the pro‐and anti‐inflammatory phases of an innate immune response.

Melatonin is fairly ubiquitously produced by immune cells, havingeither a paracrine or autocrine role that is important in the resolutionphase of an immune response. Variation in local melatonin productionmay therefore be relevant to the balancing of immune responses,which is thought to contribute to the efficacy of antipsychotics. Geneticvariation in the melatonin receptor is a susceptibility factor in schizo-phrenia (Park et al., 2011). Melatonin receptors also modulate thesusceptibility of antipsychotic induced tardive dyskinesia (Lai et al.,2011). Splenocytes from melatonin‐treated mice exhibited increasedmitogenic responses and produced higher levels of IFNγ and IL‐2(Pioli et al., 1993). Exogenous melatonin increased the production ofIL‐2, IL‐6, and IFNγ by human lymphocytes (Garcia-Mauriño et al.,

First hit: prenatal infections measles, polio, rubella, influenza bacterial infections

Central Neurocircuitry Neurochemistry

Synaptic plasticity Neurodevelopment

Neurogenesis PICs, TRYCATs

Neuroinflammation

Second hit: Stressors, trauma

immune activators

Peripheral Memory infection

O&NS , antioxidants PICs, TRYCATs Prenatal inflammation

Chronic stressorsNSS + NCI

Susceptibility genes: IL-18, IL-2FGF1, NRG-1

Fig. 1. This figure shows that immuno-inflammatory pathways may account for the higher neffects of activated microglia, oxidative and nitrosative stress (O&NS), cytokine‐induced activN‐methyl D‐aspartate receptor (NMDAr) and glutamate production. A first hit, i.e. prenatal vwith maintained activation of immuno‐inflammatory pathways coupled to increased microgladult-onset schizophrenia and could be markers of a neurodevelopmental process. Chroniimmuno-inflammatory, cell-mediated immune (CMI) and O&NS pathways and consequenpro-inflammatory cytokines (PICs) may activate the TRYCAT pathway, including increased levof the α7 nicotinic acetylcholine receptor (α7nAchr) lowers gamma‐amino‐butyric‐acidHypofunctioning of the NMDAr on GABAergic interneurons will contribute to glutamatergic dopmental driven changes in the immuno‐inflammatory and TRYCAT pathways (IL-18—intergrowth factor‐beta1, NOS—nitric oxide synthase, APP—amyloid precursor protein, BACE1—ApoE—apolipoprotein E, Notch). Activated immuno‐inflammatory responses are additionallyabovementioned processes all contribute to neuroprogressive alterations, such as reduced ne

1997); blocked lymphocyte melatonin production; and reduced IL‐2(Carrillo‐Vico et al., 2005). Therefore, at the cellular level, both endog-enous and exogenous melatonin induced IL‐2 production. Melatonincan also decrease genital infection (Rahman et al., 2005), suggestingrelevance in both the early developmental etiology of schizophrenia,as well as in the management of adult manifestations (Anderson andMaes, 2012), including the emergence of tardive dyskinesia (Shamiret al., 2001).

6.5.4. MinocyclineIn a carefully controlled clinical trial, minocycline has shown effi-

cacy in improving negative and cognitive symptoms versus antipsy-chotics alone (Levkovitz et al., 2010). Currently, it is thought thatanti‐inflammatory strategies may exert no superior effects whenimplemented in patients with longstanding disease duration (Meyer,2013–this issue; Rapoport et al., 2005). However, a better understand-ing of immuno‐inflammatory and TRYCAT pathway alterations overtime in long duration patients should considerably aid treatment.

6.5.5. Prophylactic treatments: vit D and zincProphylactic treatments focusing on maternal infection, and down-

streamoffspring immuno‐inflammatory alterations, would be expectedto substantially reduce the incidence of schizophrenia (Brown andPatterson, 2011), by as much as one‐third (Brown and Derkits, 2010).The optimization of vit D would be expected to decrease the risk andconsequences of many infections and minimize the association ofschizophrenia with seasonal fluctuations, preeclampsia and someethnic groups as well as with maternal infection (Anderson, 2011),

,

Neuroprogression Neurogenesis Myelination Synaptic plasticity

Peripheral Autoimmune responses TRYCATs: KA and QUIN O&NS , antioxidants (GSH) PICs, CMI activation

8, TNF , TGF- 1, NOS, APP, BACE1, , ApoE, Notch, etc

TRYCATs: KA and QUIN O&NS, GSH Neurotoxic PICs

Neuroinflammation

Glutaminergic signalling GABA NMDAr

7nAChr

eurodevelopmental pathology linked with gestational infections through the detrimentalation of the tryptophan catabolite (TRYCAT) pathway and consequent modulation of theiral or bacterial infections, may drive an early developmental etiology to schizophreniaia activation. Neurological soft signs (NSS) and cognitive defects (CD) frequently precedec stressors may also act as a second hit to prenatal infection. Following second hits,tly autoimmune responses may be activated. The consequent increased production ofels of TRYCATs, e.g. quinolinic acid (QUIN) and kynurenic acid (KA). KA via the inhibition(GABA)-ergic signaling, which contributes to dysregulated glutamatergic activity.

ysregulation. Many susceptibility genes for schizophrenia may interact with early devel-leukin-18, IL-28—interleukin-28, TNFα—tumor necrosis factor-α, TGF‐β1—transformingB‐site APP‐cleaving protein‐1, FGF1—fibroblast growth factor‐1, NRG-1—Neuregulin‐1,associated with O&NS, including lowered antioxidants such as glutathione (GSH). The

urogenesis, myelination and neuroplasticity, and neurotoxicity and excitotoxicity.


including the inhibition of placental inflammation (Liu et al., 2011b). VitD has a number of impacts on the immune system that would be rele-vant to the course as well as the etiology of schizophrenia. IL‐2, IL‐10and IL‐12, known to be altered in schizophrenia, are primary vit D targetgenes (Matilainen et al., 2010). Vit D and IL‐2 combine to inhibit T cellpro‐inflammatory cytokine production and promote the developmentof regulatory T cells (Jeffery et al., 2009). Also antipsychotics, especiallyclozapine, increase the risk of developing pneumonia in the early courseof the treatment (Kuo et al., in press). The optimization of vit D, and per-haps melatonin, at the initiation of antipsychotic therapy should lessenthe risk of pneumonia developing.

Animal models also suggest that the deleterious consequences ofprenatal infection/inflammation can be attenuated or prevented bythe regulation of inflammatory and O&NS processes, including viasupplementation with iron or zinc (Coyle et al., 2009). Much sufferingwill be alleviated by research focusing on preventative interventionsin the preconception (e.g. vit D) as well as pre‐ and peri‐natal periods(e.g. zinc).

7. Conclusions

Fig. 1 shows the links between prenatal infection, the immuno-inflammatory pathways, and neuroprogression in schizophrenia.Prenatal infection, both viral and microbial, has a powerful role indriving the early developmental etiology to schizophrenia. Prenatal ro-dent infections show maintained activation of immuno‐inflammatorypathways and, via IDO induction and increased availability of TRYCATsin the CNS, will modulate glia TRYCATs and subsequently patternedneuronal activity. These same inflammatory and TRYCAT pathwayswill also be differentially regulated by factors such as social isolation,trauma and CUMS that can increase the likelihood of schizophreniaon their own, but also as second hits to a primary prenatal infection.

Different perspectives of, or collected bodies of data on, the natureof schizophrenia can be synthesized within this frame of reference,including: a) increased astrocyte KA, via the inhibition of theα7nAChr, leading to hypofunctioning of the NMDAr on GABAergicinterneurons driving glutamatergic dysregulation. b) Why so manysusceptibility genes for schizophrenia are predominantly expressed inearly development, where they will interact with early developmentaldriven changes in the immuno‐inflammatory and TRYCAT pathways.c) How susceptibility genes alter the nature of glia‐neuronal interac-tions, explaining why susceptibility genes have strong overlap withdementia processes. d) How alterations in plasticity may be co‐ordinated with hypomyelination, in part via specific susceptibilitygenes. e) How maternal infection driven changes in O&NS, in con-junction with lowered endogenous anti‐oxidants, modulate inflam-matory process peripherally and centrally, in turn contributing todecreased neurogenesis and stress driven variations in local BBB per-meability. f) How the insidiousness of neuroprogression and treat-ment resistance are immune‐inflammatory and TRYCAT driven, andmay have preferential associations with different susceptibility genes. g)How the transformation of such distinct stressors as CUMS, social isola-tion and trauma may be transformed into a common immune andTRYCAT language, to then act as a second hit to prenatal infection. h)How prenatal infection and stress may co‐ordinate local structuralchanges via changes in amygdala development and activity. i) Howchanges in miR‐132 can be downstream from TRYCAT activation.

Such a frame of reference also provides numerous directions forfuture research, including the role of γδ T cells and IL‐28 in mediatingand modulating the longer‐term consequences of prenatal infection.A fuller understanding of the changes induced by different types ofmaternal infection on fetal immune and TRYCAT parameters will aidthe development of post‐natal preventative interventions in childrenat risk of developing schizophrenia. Likewise a fuller appreciation ofthe role of altered immuno‐inflammatory and TRYCAT activities in

the course of schizophrenia, and perhaps biologically defined sub-types, should lead to better targeted treatment.

Many psychiatric medications, including mood stabilizers, antipsy-chotics and anti-depressants have been shown to be efficacious in awide spectrum of psychiatric and neuroprogressive disorders includingautism, schizophrenia, depression, bipolar disorder, Alzheimer's andmultiple sclerosis (Anderson and Rodirguez, 2011). This apparent lackof specificity suggests that the symptoms of a wide range of disordersas well as their treatments may share aspects of biology and mecha-nisms of action that defy current symptom‐based diagnostic and neu-ron‐centric therapeutic schema (Anderson, 2011; Bartzokis, 2012).The role of the immuno‐inflammatory system, in both etiology andcourse, and driven by variations in cytokines and the TRYCAT pathwaysseems crucial in both differentiating and integrating biological processthat overlaps and differentiates these disorders, with consequent treat-ment implications.

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