Involvement of Neuroinflammation during Brain Development ...jpet.aspetjournals.org/content/jpet/358/3/504.full.pdfthecerebellum,midbrain,fusiformgyrus,andprefrontalcortex in ASD adults

1521-0103/358/3/504–515$25.00 http://dx.doi.org/10.1124/jpet.116.234476THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 358:504–515, September 2016Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics

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Involvement of Neuroinflammation during Brain Development inSocial Cognitive Deficits in Autism Spectrum Disorderand Schizophrenia

Yutaka Nakagawa and Kenji ChibaInnovative Research Division, Mitsubishi Tanabe Pharma, Yokohama, Japan

Received April 18, 2016; accepted July 5, 2016

ABSTRACTDevelopment of social cognition, a unique and high-order func-tion, depends on brain maturation from childhood to adulthoodin humans. Autism spectrum disorder (ASD) and schizophreniahave similar social cognitive deficits, although age of onset ineach disorder is different. Pathogenesis of these disorders iscomplex and contains several features, including genetic riskfactors, environmental risk factors, and sites of abnormalitiesin the brain. Although several hypotheses have been postulated,they seem to be insufficient to explain how brain alterationsassociated with symptoms in these disorders develop at distinctdevelopmental stages. Development of ASD appears to be relatedto cerebellar dysfunction and subsequent thalamic hyperactiva-tion in early childhood. By contrast, schizophrenia seems to be

triggered by thalamic hyperactivation in late adolescence,whereas hippocampal aberration has been possibly initiated inchildhood. One of the possible culprits is metal homeostasisdisturbances that can induce dysfunction of blood-cerebrospinalfluid barrier. Thalamic hyperactivation is thought to be induced bymicroglia-mediated neuroinflammation and abnormalities of intra-cerebral environment. Consequently, it is likely that the thalamichyperactivation triggers dysregulation of the dorsolateral pre-frontal cortex for lower brain regions related to social cognition.In this review, we summarize the brain aberration in ASD andschizophrenia and provide a possible mechanism underlyingsocial cognitive deficits in these disorders based on their distinctages of onset.

IntroductionMicroglial cells contribute to immune surveillance in the

central nervous systems (CNS), and polarization of microglialsubsets (M1 andM2) plays an important role in controlling thebalance between promotion and suppression in neuroinflam-mation (Ransohoff and Perry, 2009; Kettenmann et al., 2011;Mikita et al., 2011; Saijo and Glass, 2011). M1 microglial cellscan promote neuroinflammation and subsequent neural net-work dysfunction in the CNS, whereas M2 microglia areimplicated in inhibiting inflammation and restoring homeo-stasis (Mosser and Edwards, 2008; Gordon and Martinez,2010). As we reported previously, imbalance of M1 and M2microglia appears to be closely related to mood aberration of

major depressive disorder and bipolar disorder (Nakagawaand Chiba, 2014, 2015). Autism spectrum disorder (ASD) isdefined by deficits in social communication interaction andbehavioral flexibility, manifesting in early childhood (Volkmaret al., 2014). Eighteen surveys conducted according to theDiagnostic and Statistical Manual of Mental Disorders, fourthedition, criteria demonstrated that estimates of the rate ofASD range from 10 in 10,000 to 16 in 10,000, whereas themostrecent study estimated the prevalence in the United Statesas 11.3 in 1,000, suggesting that the prevalence of ASD isincreasing (Volkmar et al., 2014). Parents of children withASD have often reported that the first sign of a problem withtheir child was the delay of language in the second year of life(Tager-Flusberg, 2000). Social cognitive deficits are a hallmarkcharacteristic of ASD and schizophrenia (Couture et al., 2006;Meyer et al., 2011a).Schizophrenia is characterized by positive, negative, and

cognitive symptoms and afflicts approximately 1% worldwide;it develops in late adolescencemost frequently (Stahl, 2013). It

The authors declare no conflict of interest. Both authors are employees ofMitsubishi Tanabe Pharma and have not received financial support from anyother institution.

dx.doi.org/10.1124/jpet.116.234476.

ABBREVIATIONS: ASD, autism spectrum disorder; BBB, blood-brain barrier; BCB, blood-CSF barrier; [11C](R)-PK11195, [11C] (R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide); CCL, CC-chemokine ligand; CNS, central nervous system; CNTNAP2,contactin-associated protein-like 2; CSF, cerebrospinal fluid; CVO, circumventricular organ; CXCL, CXC-chemokine ligand; DLPFC, dorsolateralprefrontal cortex; FFA, fusiform face area; FOXP2, forkhead box P2; IFN-g, interferon-g; IL, interleukin; PrPC, cellular prion protein; PrPSc, adisease-associated isoform of the prion protein; PSD-95, postsynaptic density protein 95; SOD-1, superoxide dismutase-1; STG, superior temporalgyrus; STS, superior temporal sulcus; VLPFC, ventrolateral prefrontal cortex; VMPFC, ventromedial prefrontal cortex.

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is postulated that dopamine hyperactivity in the nucleusaccumbens induced by hypofunction of glutamate receptorsin the prefrontal cortex and hippocampus is related to positivesymptoms, whereas hypoactivation of dopamine and gluta-mate neurons in the prefrontal cortex contributes to negativesymptoms (Stahl, 2013). In contrast, according to the neuro-developmental hypothesis, the etiology of schizophrenia ap-pears to involve pathologic processes that are caused bygenetic and environmental risk factors and begin beforethe brain fully matures (Weinberger, 1986; Marenco andWeinberger, 2000).Pathogenesis of these disorders is complex and contains

several features, including genetic risk factors, environmentalrisk factors, and sites of abnormalities in the brain (Hultmanet al., 1999; Gardener et al., 2011; Miles, 2011; Onore et al.,2012). Recently, Meyer et al. (2011a), focusing on similaritiesand differences between schizophrenia and ASD, implied thatdisturbed neurodevelopment by maternal infection and suc-ceeding prenatal neuroinflammation is shared by ASD andschizophrenia, whereas persistent and latent neuroinflamma-tion contributes to onsets of ASD and schizophrenia, respec-tively. However, these hypotheses seem not to clarify howbrain alterations associated with symptoms in these dis-orders develop at distinct developmental stages. Therefore,in this article, we summarize the brain aberration and relatedneuroinflammation in early and chronic phases of ASD,discuss similarities and differences between social cognitivedeficits in ASD and those in schizophrenia, and provide apossible mechanism underlying the social cognitive deficits inthese disorders.

ASD and NeuroinflammationGenetic Risk Factors. Although there has been con-

siderable debate in etiology of ASD, the genetic basis of thisdisorder is supported by several twin studies (Rosenberg et al.,2009; Frazier et al., 2014). Much attention has been focusedon a relationship between ASD and a transcriptional gene,forkhead box P2 (FOXP2), which is closely related to languageability (Bowers and Konopka, 2012). FOXP2 protein regulatesgene expression ofMET (Mukamel, et al., 2011) and contactin-associated protein-like 2 (CNTNAP2) (Arking et al., 2008;Bowers and Konopka, 2012). During gestation, MET gene isselectively expressed in the temporal and occipital lobes, whichcontribute to verbal communication, implying that METplays an important role in development of language ability(Mukamel et al., 2011). The CNTNAP2 encodes a cell adhesionmolecule of neurexin subfamily and is highly expressed infrontal lobe circuits in the developing human brain (Arkinget al., 2008). It has been reported that common variants inCNTNAP2 are associated with several allied neurodevelop-mental disorders, including ASD (Scott-Van Zeeland et al.,2010). FOXP2 mutant mice show ASD-like phenotypes, suchas reduced or atypical vocalizations and impairments oflearning performances (Shu et al., 2005; Fujita et al., 2008;Kurt et al., 2012).Other studies demonstrated that ASD symptoms are associ-

ated with gene variations of neuroligin, neurexin, Src homologyand multiple ankyrin repeat domain 3, and cell adhesionmolecule 1 (Zhiling et al., 2008; Bourgeron, 2009; Fujita-Jimboet al., 2015). The variations of these synaptic cell adhesionmolecules seem to induce an imbalance of excitatory and

inhibitory receptors and synaptic pruning deficits (Lisé andEl-Husseini, 2006; LeBlanc and Fagiolini, 2011). In the pro-cess of synaptic pruning, upregulation of myocyte enhancerfactor 2 can lead to ubiquitination of postsynaptic densityprotein 95 (PSD-95) in the postsynaptic density, and, sub-sequently, the degradation of ubiquitinated PSD-95 resultsin a synapse elimination (Caroni et al., 2014). Interestingly,mutated neuroligin 3 or cell adhesion molecule 1 protein upre-gulates C/EBP-homologous protein, a marker of endoplasmicreticulum stress, suggesting that the synaptic pruning deficitsinduce endoplasmic reticulum stress and neuroinflammationin ASD (Fujita et al., 2010; Fujita-Jimbo et al., 2012, 2015).Consequently, these genetic factors presumably influencefunction of neural circuitry of social cognition in combinationwith environmental risk factors.Environmental Risk Factors. Air pollutants, pesticides,

polychlorinated biphenyls, solvents, and glyphosate appearto be associated with development of ASD (Sealey et al., 2016).A possible relationship is shown between ASD severity andblood or hair levels of heavy metals, including mercury andlead (Rossignol et al., 2014). A recent study revealed thatsome of ASD may be caused by maternal antibodies to fetalbrain antigens such as cypin, which, along with PSD-95,can regulate dendritic branching of hippocampal neurons(Braunschweig et al., 2013). Sodium valproate, an anticonvul-sant and a mood stabilizer, induces fetal neurodevelopmentaberration in animals, including humans, higher incidence ofASD in humans, and ASD-like phenotypes such as reducedsocial interaction and increased repetitive behaviors in ro-dents (Roullet et al., 2013). There are many prenatal andpostnatal risk factors, as follows: maternal medication use,C-reactive protein levels, hypertension, hemorrhage, infec-tion, depressive symptomatology, food, gestational diabetes,parental age at birth, prolonged labor, fetal distress, birthinjury or trauma,multiple birth, low birth weight, etc. (Glassonet al., 2004; Gardener et al., 2009, 2011; Lupien et al., 2011;Patterson, 2011; Guinchat et al., 2012; Neggers, 2014; Xianget al., 2015).Metal Homeostasis Disturbances. It is highly probable

that a well-balanced diet plays an essential role in develop-ment and maintenance of brain functions, because goodnutrition is a cornerstone of goodhealth,whereas poor nutritionis associated with reduced immunity, impaired physical devel-opment, and reduced productivity (World Health Organization,2016). Children with ASD often have restricted diets that canlead to nutrient deficiencies with brain metal homeostasisdisturbances (Bilgiç et al., 2010; Sidrak et al., 2014). Irondeficiency is one of the most prevalent types of malnutrition,affecting probable two billion people in the world, and pregnantwomen and young children are affected most severely, becausepregnancy and infant growth demand iron (World HealthOrganization, 2016). Iron is required for basic cellular functionsin all of the tissues, especially in the brain and muscle, andis critically important for the oxygen-carrier function of hemo-globin in red blood cells (Breymann, 2015). In the brain, iron istransported by transferrin or divalentmetal transporter-1 fromthe peripheral blood and is essential for the activity of severalenzymes involved in myelination process and monoamineneurotransmitter synthesis (Dusek et al., 2015). Iron deficiencyis suggested to be related to development of ASD (Bilgiç et al.,2010; Sidrak et al., 2014). Lower iron concentrations in theblood appear to induce transport of neurotoxic manganese

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instead of iron into the brain (Gunter et al., 2013; Duseket al., 2015).When zinc levels are decreased and conversely copper levels

are increased in the blood during pregnancy, prevention offetal development would be introduced (Faber et al., 2009).The imbalance of zinc and copper levels may deteriorateFOXP2 functions and induce language disability, becauseFOXP2 contains zinc finger domain (Bowers and Konopka,2012). Indeed, it has been reported that ASD children showreduced zinc levels in their hairs and low blood zinc/copperratio (Faber et al., 2009; Yasuda et al., 2011, 2013). Takentogether, it is possible that metal homeostasis disturbancesare one of the primary culprits of ASD.Involvement of Neuroinflammation. A ligand for the

peripheral benzodiazepine receptor, [11C] (R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([11C](R)-PK11195), can be used for the imaging of activated micro-glia cells with positron emission tomography (Banati, 2002). Ithas been reported that [11C](R)-PK11195–binding potentialvalues are significantly higher in the brain regions, includingthe cerebellum,midbrain, fusiform gyrus, and prefrontal cortexin ASD adults as compared with controls (Suzuki et al., 2013).In the visual cortex in autopsy brains, microglial densities aresignificantly greater in individuals with ASD versus controls(Tetreault et al., 2012). An immunohistochemical study revealedthat a marked activation of microglia and astrocytes in themiddle frontal and anterior cingulate gyri and cerebellum isobtained at autopsy from ASD subjects (Vargas et al., 2005).Similarly, microglial cells are markedly activated in the dorso-lateral prefrontal cortex (DLPFC) of ASD individuals (Morganet al., 2010). Risperidone in combinationwith a cyclooxygenase-2inhibitor, celecoxib, showed a superior efficacy as comparedwith monotherapy of risperidone in a randomized double-blind placebo-controlled clinical study in ASD children(Asadabadi et al., 2013). From these results, neuroinflam-mation mediated by M1 microglia appears to be associatedwith ASD.Postmortem studies revealed prominent microglia activa-

tion and increased proinflammatory cytokines and chemokines,including interferon-g (IFN-g), interleukin (IL)-1b, IL-6,IL-12p40, tumor necrosis factor-a, and CC-chemokine ligand2 (CCL2) in the brain, particularly in the frontal cortex,cerebellum, and cerebrospinal fluid (CSF) of ASD individuals(Vargas et al., 2005; Li et al., 2009; Morgan et al., 2010; Onoreet al., 2012). Similarly, the levels of IL-1b, IL-6, IL-8, IL-12p40,CCL2, CCL5, and CCL11 are significantly increased in theplasma of ASD individuals (Ashwood et al., 2011a, b). Theincreased cytokine levels were predominantly in children whohad a regressive form of ASD and were associated with moreimpaired communication and aberrant behaviors (Ashwoodet al., 2011a, b). Furthermore, BTBR T1tf/J mice with genemutation in kynurenine 3-hydroxylase (Kmo) related to neuro-protective actions show elevated levels of proinflammatorycytokines, including IL-1b and IL-6 in the cerebellum andASD-like phenotypes such as reduced social interactions andimpaired juvenile play (McFarlane et al., 2008; Heo et al., 2011).In contrast, the levels of IL-4 and IL-10 in the plasma showed nodifference between ASD and control subjects (Ashwood et al.,2011b). The levels of transforming growth factor-b in ASDbloodare significantly lower as compared with typically developingcontrols and are negatively correlated with psychologic symp-tom severity (Okada et al., 2007; Ashwood et al., 2008).

Therefore, it is highly possible that neuroinflammationmediated by M1 microglia is associated with symptoms ofASD based on imbalance of proinflammatory M1 and anti-inflammatory M2 polarization states of microglia. Our view isalong the lines of previous hypotheses that the imbalance ofM1/M2 polarization of microglia is implicated in neuroinflam-mation and disruption of excitatory versus inhibitory balancein the brain of ASD (Gottfried et al., 2015; Koyama andIkegaya, 2015).Disturbances in the Blood-Brain Barrier. The blood-

brain barrier (BBB) has a unique barrier structure betweenthe lumen of cerebral blood vessels and brain parenchyma.The endothelial cells have luminal tight junction and aresurrounded by basement membrane and the pericytes. Aroundall of these structures are the astrocytic end feet processes fromnearby astrocytes. The interaction among vascular endothelialcells, pericytes, and astrocytes plays an important role inmaintenance of BBB functions (Abbott et al., 2006; Bonkowskiet al., 2011). It is possible that BBB dysfunction contributesto major depressive disorder and schizophrenia (Shalev et al.,2009).Maternal hyperglycemia and hypertension are often asso-

ciated with activation of inflammatory cells, inducing abnor-malities in capillary endothelial cells of the brain (Jackson,2011). In the inflamed capillaries, proinflammatory cytokinesand mediators contribute to the polarization and recruitmentof M1 macrophages (Jackson, 2011). At early phase, M1macrophages appear to remove injured vascular endothelialcells by phagocytosis (Jackson, 2011; Phillipson and Kubes,2011); however, under insufficient M2 condition, M1 macro-phages can probably induce prolonged inflammation and de-struction of BBB. The BBB possesses manganese sensitivity(Bornhorst et al., 2012), suggesting that disequilibrium of ironand manganese levels is presumably associated with dysfunc-tion of BBB directly. Imbalance of zinc and copper levelsmay contribute to dysfunction of astrocytes because astrocytesexpress copper, zinc (CuZn) superoxide dismutase-1 (SOD-1)activity (Chen et al., 2006). Taken together, it is likely thatdysfunction of BBB is caused by multiple prenatal and post-natal risk factors. Because BBB function is immature at earlydevelopmental stages (Saunders et al., 2014), cerebral neuralcells in fetuses, infants, and young children are presumablyvulnerable to these factors. Therefore, it is possible that BBBdisturbances are related to ASD.Disturbances in the Blood-CSF Barrier. The blood-

CSF barrier (BCB) lies between the choroid plexus vessels incircumventricular organs (CVOs) and the CSF (Choi and Kim,2008; Benarroch, 2011; Lun et al., 2015). The CVOs are foundto be located around the cerebral ventricles, and the CVOswith BCB are characterized by lack of BBB properties (Choiand Kim, 2008; Benarroch, 2011). In the BCB, tanycytes,highly specialized ependymal cells, have tight junction andplay regulatory roles in interaction among the blood, brainparenchyma, and CSF (Benarroch, 2011; Langlet et al., 2013).Tanycytes contribute to monitoring the CSF composition (Sisóet al., 2010; Benarroch, 2011), and these cells seem to bevulnerable to imbalance of zinc and copper levels becausetanycytes express CuZn SOD-1 (Peluffo et al., 2005). Further-more, the BCB is thought to be a major route for manganeseinto the CSF because the increased blood manganese levelscan induce more severe dysfunction of the BCB rather thanBBB (Bornhorst et al., 2012). Therefore, it is highly probable

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that maternal disturbances of cellular metal homeostasispredominantly induce dysfunction of tanycytes in the BCBand subsequent neuroinflammation that triggers aberration ofneural network in fetuses, infants, and young children (Fig. 1).

Social Cognitive Deficits in ASDCognitive function such as self-regulation and social cogni-

tion enables humans to make plans and regulate actions insocial situations appropriately (Heatherton and Wagner,2011). This unique cognitive function depends on brainmaturation from childhood to adulthood in humans (Lebelet al., 2008; Catts et al., 2013). Therefore, it is likely thatimmaturity negatively impacts high-order cognition acquiredat each developmental stage.Dysfunction of the Cerebellum. Young children with

ASD (2–4 years of age) show a significant increase in cerebellarvolume as compared with typically developing children,whereas cerebellar volume of ASD schoolchildren and adoles-cents is similar to or rather smaller than controls (Sparks et al.,2002; Allen, 2005; Anagnostou and Taylor, 2011). A diffusion

tensor imaging study to investigate brain anatomic connectivityindicated a significant increase in fractional anisotropy, thedeviation from pure isotropic diffusion of water mobility, in thebrain regions including cerebellum of young children with ASD(1–6 years of age) (Weinstein et al., 2011). In contrast, fractionalanisotropy in the cerebellum is decreased inASDschoolchildren(6–12 years old) (Brito et al., 2009). Serotonin transporterbinding is reduced in several brain regions, including cerebel-lum of ASD adults (Nakamura et al., 2010). Furthermore, [11C](R)-PK11195–binding values are significantly higher in thebrain regions including cerebellum of ASD adults as comparedwith those of controls (Suzuki et al., 2013). From these results,it is possible that neuronal hyperactivation and neuroinflam-mation occur in the cerebellum of young children with ASD,subsequently leading to reduction of neuronal activity andatrophy with persistent neuroinflammation in the cerebellumof ASD schoolchildren, adolescents, and adults.The cerebellum is involved in body and limb movement,

executive and cognitive functions, and language ability (Koziolet al., 2014; Wang et al., 2014). ASD individuals often showmotor abnormalities consistent with cerebellar dysfunctionthat occurs in young children and is persistent over time (LeeandBo, 2015). Although cerebellar lesions are unlikely to resultin profound cognitive deficits in adults, cerebellar abnormal-ities at earlier ages lead to more conspicuous cognitive andaffective changes, diagnosed as cerebellar cognitive-affectivesyndrome (Wang et al., 2014). Cerebellar cognitive-affectivesyndrome is characterized by disturbances of executive func-tion, impaired spatial cognition, personality change, andlinguistic difficulties (Schmahmann and Sherman, 1998). Ithas been hypothesized that the cerebellum plays a pivotal rolein cognition in young children within the critical period (2–4years of age) and contributes to body and limb movement atevery developmental stage (Wang et al., 2014). Thus, one couldspeculate that cerebellar aberration in young children isassociated with initiation of social cognitive deficits in ASD.As mentioned in the above section, impaired cellular metal

homeostasis can induce disturbances of cerebral ventriclesand contributes to functional or structural alterations in thebrain. Because the cerebellum is located adjacent to the fourthventricle and the cerebral ventricles are partly surrounded bythe choroid plexus in young children (Su and Young, 2011;Liddelow, 2015), impaired cellular metal homeostasis proba-bly induces hyperactivation of the cerebellum via dysfunctionof choroid plexus and fourth ventricle in young children withASD. Neuronal hyperactivation can trigger M1 polarization ofmicroglia in the cerebellum, and thenM1microglial-mediatedneuroinflammation and neural network dysfunction mayextend to the related tissues under inhibition in the M2 state.Consequently, it is possible that imbalance between M1 andM2 polarization of microglia plays an important role in theprogression of ASD (Nakagawa and Chiba, 2014, 2015).It is unlikely that symptoms of ASD can be caused by

abnormalities in a single brain region because a significantreduction in total gray matter volume and a marked increasein cerebral ventricular volume are observed in ASD school-children and adolescents (McAlonan et al., 2005). There areneuronal connections between the cerebellum and other brainregions (Mazzola et al., 2013; Rogers et al., 2013; Koziol et al.,2014). To understand symptoms, initiation, and progression ofASD more precisely, it is important to analyze the neuropatho-logical relation between the cerebellum and other brain regions.

Fig. 1. The cerebral ventricles, BBB, and BCB. (A) The lateral, third, andfourth ventricles neighbor brain regions such as hippocampus, amygdala,thalamus, and cerebellum. (B) The BBB has a pivotal role in sufficientsupply of oxygen and nutrients to neurons and consists of the pericytes,end foot of astrocytes, and vascular endothelial cells that have luminaltight junction. (C) In the BCB, tanycytes, highly specialized ependymalcells, have tight junction and play regulatory roles in interaction amongthe blood, brain parenchyma, and CSF. Brain tissues with BCB arecharacterized by lack of BBB properties. Astrocytes and tanycytes expressCuZn SOD-1.


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Dysfunction of the Thalamus. Like the cerebellum, theamygdala and hippocampus were enlarged in children withASD as compared with control subjects, whereas no differ-ences were found in adolescent amygdala volumes (Sparkset al., 2002; Schumann et al., 2004). In contrast, atrophy andreduction of serotonin transporter binding in the thalamuswere reported in ASD from late childhood to adulthood(Tsatsanis et al., 2003; Hardan et al., 2006; Nakamura et al.,2010; Tamura et al., 2010). Higher microglial activity is foundin the thalamus of ASD adults (Suzuki et al., 2013). Fromthese results, it is presumed that in young children with ASD,neuroinflammation is initially induced in the thalamus, and,subsequently, persistent neuroinflammation induces thalamicatrophy in schoolchildren, adolescent, and adults. Because thethalamus neighbors the third ventricle, dysfunction of thethalamus in ASD may be related to impaired cellular metalhomeostasis and BCB disruption (Sisó et al., 2010).The thalamus plays a key role in sensory gate (Geyer and

Vollenweider, 2008). Both auditory and visual stimuli fromperipheral organs are sent to the thalamus, and then to theprimary auditory or visual area in the cerebral cortex (Tamiettoand de Gelder, 2010; Hackett, 2015). Functions of the thalamusare impaired in ASD schoolchildren, adolescents, and adults(Hardan et al., 2008; Lai et al., 2010). Significant decreases incerebellar activity and cerebellum-thalamus connectivity areinduced in a light or mild motor performance such as 20 fingertaps for each hand in ASD schoolchildren (Mostofsky et al.,2009). In contrast, ASD individuals show significantly increasedactivity in the cerebellum relative to control subjects when theyperform a rather complex motor task, in which they hold ajoystick and press a button with the thumb according toinstruction (Allen et al., 2004). From these results, it is likelythat, in ASD, neural network activities between the cerebellumand thalamus are decreased at resting state, whereas thispathway is activated when a task is provided. In daily life ofASD individuals, activities of the cerebellum and cerebellum-thalamus pathway appear to be increased because socialcommunication is always necessary.Aberration of Verbal Communication. Underconnec-

tivity in the thalamo-frontal pathway is induced in ASD school-children and adolescents (Cheon et al., 2011). In contrast,functional overconnectivity between the thalamus and tem-poral lobe occurs in ASD schoolchildren and adolescents,although underconnectivity is found for other cortical regions(Nair et al., 2013). Therefore, it is possible that hyperactiva-tion of the thalamus-temporal lobe connections is due tothalamo-frontal underconnectivity, and that dysconnectivityof these pathways is associated with ASD symptoms.ASD adults fail to activate the superior temporal sulcus

(STS)/superior temporal gyrus (STG) in response to humanvocal sounds, whereas they show a normal activation patternin response to nonvocal sounds (Gervais et al., 2004). Under-connectivity is induced between the STS/STG and dopami-nergic reward pathway, including the ventral tegmental areaand nucleus accumbens in ASD schoolchildren (Abrams et al.,2013). These results suggest that chronic hyperactivationof the thalamus-temporal lobe connections induces desen-sitization of the STS/STG, and that underconnectivity ofSTS/STG-reward pathway impairs the ability of ASD childrento experience speech as a pleasurable stimulus, subsequentlyleading to deterioration of language and social skills. It ispossible that the definite reduction of STS/STG reactivity to

human vocal sounds in ASD is caused by disturbances of theprefrontal cortex, which regulates functions of the STS/STGand is implicated in social cognition.There are neuronal connections between the STS/STG

and ventrolateral prefrontal cortex (VLPFC) that integratesocial cognitive information (Takahashi et al., 2007; Levy andWagner, 2011; Lai et al., 2012). Underconnectivity betweenthe temporal cortex and VLPFC occurs in adult ASD (Satoet al., 2012). In addition, VLPFC activity is significantlyreduced in schoolchildren and adolescents with ASD relativeto controls during speech stimulation (Lai et al., 2012).Accordingly, it is presumable that in daily life of ASD children,cerebellar and thalamic hyperactivation induces dysfunctionof the STS/STG and VLPFC, leading to a failure to integrateverbal information, which probably persists in adulthood.Aberration of Nonverbal Communication. The thala-

mus, fusiform face area (FFA), STS/STG, andVLPFCalso playa pivotal role in nonverbal communication, including facialexpressions, gestures, eye contact, and body language (Redcay,2008; Sato et al., 2012). These visual signals from the thalamusare sent to the visual cortex and FFA (Tamietto and de Gelder,2010; Blank et al., 2011). Microglial activity is increased in thevisual cortex/FFA of ASD individuals (Tetreault et al., 2012;Suzuki et al., 2013). Therefore, it is probable that thalamichyperactivation induces microglia-mediated neuroinflamma-tion and aberration of the visual cortex and FAA.There are neuronal connections between the visual cortex/FFA,

STS/STG, and VLPFC (Kreifelts et al., 2007; Blank et al.,2011; Sato et al., 2012). The STS/STG plays a key role indirect structural connections between verbal- and nonverbal-recognition areas (Kreifelts et al., 2007; Blank et al., 2011).Functional underconnectivity between the visual cortex andSTS/STG or VLPFC occurs in ASD adults in response toemotional stimuli (Sato et al., 2012; Khan et al., 2013). Takentogether, we hypothesize that abnormalities of verbal andnonverbal communication in ASD are due to cerebellar andthalamic hyperactivation and subsequent dysfunction of thevisual cortex, FAA, STS/STG, and VLPFC.Hippocampus-Amygdala Interaction and Emotional

Responses. The hippocampus is thought to be vulnerable todevelopmental aberration during prenatal stage (Abernethyet al., 2002; Beauchamp et al., 2008). BCB abnormalitiesaccompanying with impaired cellular metal homeostasis maybe related to hippocampal dysfunction because of neighboringthe hippocampus and lateral ventricle (Dziegielewska et al.,2001; Kiernan, 2012).The reciprocal interaction between amygdala and hippo-

campus contributes to emotion, emotion-related memory, andneurocognition, etc. (Potschka et al., 2011; Orsini and Maren,2012). Hyperactivation of the amygdala occurs in ASD adultsduring identification of previously viewed faces (Kleinhanset al., 2008; Monk et al., 2010; Dichter, 2012). Social impair-ment is positively correlated to amygdala activation but isnegatively related to amygdala-FFA connectivity in ASD(Kleinhans et al., 2008; Dichter, 2012). Development of faceperception and social cognitive skills is supported by theamygdala-FFA system (Schultz, 2005; Vuilleumier andPourtois,2007). Therefore, underconnectivity of amygdala-FFA path-way in ASD appears to induce overconnectivity between theamygdala and brain regions other than FFA.The ventromedial prefrontal cortex (VMPFC) plays a crit-

ical role in regulation of amygdala activity (Blair, 2013;


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Motzkin et al., 2015). ASD subjects show increased neuronalactivities in theVMPFCand amygdala in response to emotionalstimuli and higher microglial activity in the VMPFC (Monket al., 2010; Suzuki et al., 2013). Poor performance on the Iowagambling task is found inASD schoolchildren and adolescents,suggesting lower VMPFC functions (Sawa et al., 2013).Accordingly, it is likely that long-lasting hyperactivation ofthe amygdala induces VMPFC dysfunction, which is mediatedby neuroinflammation. The dysfunction of VMPFC probablycauses dysregulation between the VMPFC and amygdala andmay induce aberration of emotional responses in ASD.The DLPFC and Top-Down Control. Top-down control

of lower brain regions by the DLPFC enables us to makeappropriate planning and action in social situations basedon integration of information, including verbal and non-verbal cognition, workingmemory, and evaluation of immediateas well as future outcomes (Tanaka et al., 2004;Weissman et al.,2008; Heatherton and Wagner, 2011). The number and size ofneuron are significantly increased in theDLPFC of ASD subjects(Courchesne et al., 2011). Compared with typically developingsubjects, ASD schoolchildren and adolescents perform signifi-cantly worse on DLPFC task (Dawson et al., 1998; Sawa et al.,2013). The ratio of N-acetyl-aspartate/creatine/phosphocreatinein the DLPFC is positively correlated with social ability scores inASD children and adolescents (Fujii et al., 2010). From theseresults, hypoactivation of the DLPFC appears to occur in ASDlike other psychiatric disorders (Hassel et al., 2008; Kang et al.,2012; Palaniyappan et al., 2013), and disturbances in top-downcontrol of lower brain regions by DLPFC may result in socialcognitive deficits.Taken together, we hypothesize that impaired cellular

metal homeostasis, one of the primary culprits, can initiallyinduce disturbances of the BCB rather than BBB and

subsequent cerebellar hyperactivation in young children withASD. The cerebellar hyperactivation appears to increasethalamic activity and connectivity between the thalamusand STS/STG because of underconnectivity of the thalamo-frontal pathway, thereby resulting in dysfunction of STS/STGand VLPFC. In contrast, hyperactivation of the hippocampusand amygdala probably causes dysregulation of VMPFC re-sponsible for emotional responses. These events in childhoodmay induce hypoactivation of the DLPFC, which controls lowerbrain regions related to social ability, and then lead to socialcognitive deficits in ASD.

Social Cognitive Deficits in SchizophreniaThe major clinical, biochemical, and genetic features in

ASD and schizophrenia are summarized in Table 1. Althoughcontribution of pathogenic genes is different in these disorders,similar characteristics are seen in social cognitive deficits;disturbances in glutamate, g-aminobutyric acid, and dopamineneurotransmission; and increasing proinflammatory responses.Dysfunction of the Hippocampus and Amygdala. Findings

concerning cerebellar aberration have been controversial inschizophrenia, unlike ASD (Bottmer et al., 2005). In schizo-phrenia, cerebellar disturbances contribute to neurologicalsoft signs, such as observable defects in sensory integration,motor coordination, and behavioral inhibition, which arelargely distinct from the core symptoms (Bottmer et al., 2005;Chan et al., 2010; Shinn, et al., 2015). Accordingly, it is unlikelythat cerebellar aberration is associated with cognitive deficitsin schizophrenia.Individuals with at-risk mental state and patients with the

first-episode or chronic schizophrenia have lower volumes ofseveral brain regions including the hippocampus persistently

TABLE 1Comparison of clinical, biochemical, and genetic characteristics between ASD and schizophrenia

ASD

Clinical Behavioral flexibility, delay of language, social cognitive deficits.a

Worse performance than schizophrenia children in the theory ofmind task.b Manifests in early childhood.a

Biochemical Disturbances in glutamate, GABA, and dopamineneurotransmission.c Increases in proinflammatory cytokine (IL-1b,IL-6, TNF-a, IFN-g) levels in the brain, CSF, and blood.d Noalterations in anti-inflammatory cytokine (IL-4, IL-10) levels in theblood.e

Genetic CNTNAP2, NLGN, NRXN, SHANK3, CADM1, etc.f

SchizophreniaClinical Positive, negative, cognitive symptoms (social cognitive deficits).g

Develops in late adolescence most frequently.g

Biochemical Disturbances in glutamate, GABA, and dopamineneurotransmission.g Increases in proinflammatory cytokine (IL-1b,IL-6, TNF-a) levels in the brain, CSF, and blood.h Reduction of anti-inflammatory cytokine (IL-10, IL-13) levels in the CSF and blood.h

Genetic DISC1, DTNBP1, NRG1, DRD2, HTR2A, COMT, etc.i

CADM1, cell adhesion molecule 1; COMT, catechol-O-methyltransferase; DISC1, disrupted in schizophrenia 1; DRD2,dopamine receptor D2; DTNBP1, dystrobrevin-binding protein 1; GABA, g-aminobutyric acid; HTR2A,5-hydroxytryptamine (serotonin) receptor 2A; NLGN, neuroligin; NRG1, neuregulin 1; NRXN, neurexin; SHANK3, Srchomology 3 and multiple ankyrin repeat domain 3; TNF-a, tumor necrosis factor-a.

aVolkmar et al., 2014.bPilowsky et al., 2000.cMoney and Stanwood, 2013.dOnore et al., 2012.eAshwood et al., 2011b.fBourgeron, 2009.gStahl, 2013.hMeyer et al., 2011b.iGejman et al., 2010.


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(Borgwardt et al., 2007; Chan et al., 2011). In addition, signifi-cantly reduced hippocampal volume with relatively higherplasmaIL-6 levels is induced inantipsychotic-naive schizophreniapatients with polymorphism IL-6 gene, implying that hippo-campal aberration caused by elevated IL-6 is the neurodevelop-mental origin of schizophrenia (Kalmady et al., 2014). Similarly,

higher IL-6 response bymaternal immune activation in prenatalstage is suggested to be associated with brain alterations toinitiate schizophrenia (Brown, 2011). Therefore, the hippocampusappears to be a possible brain region to initiate schizophrenia.The onset of psychosis is frequently preceded by weeks,

months, or years of prodromal symptoms, including deficits in

Fig. 2. A possible mechanism underlying social cognitive deficits in ASD and schizophrenia on their distinct ages of onset. (A) Social cognitive functionsdevelop accompanying with human brain maturation from childhood to adulthood and are related to increases in myelination of white matter tractsbetween the prefrontal cortex and other brain regions. (B) In ASD, impaired cellular metal homeostasis, one of the primary culprits, can inducedysfunction of the BCB rather than BBB, thereby leading to cerebellar aberration and subsequent thalamic hyperactivation in childhood. In the nextstep, the overconnectivity is induced between the thalamus and temporal lobe (STS/STG) because of underconnectivity of the thalamo-frontal pathway.The thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and presumably leads to dysfunction of the prefrontalcortex, including DLPFC, which regulates functions of lower brain regions contributing to social cognition. In schizophrenia, in contrast, hippocampalaberration can occur in childhood and result in succeeding hyperactivation of the thalamus in late adolescence. The thalamic hyperactivation appears tobe promoted due to immaturity of the fronto-temporal pathway and finally leads to DLPFC dysfunction with a similarity to ASD. (C) The cerebellum andprefrontal cortex are involved differently in social cognitive functions based on the maturation of the brain. The cerebellum appears to play apredominant role in cognitive functions at young childhood because the cerebellum has fully maturated at that time. In contrast, the prefrontal cortex isthought to contribute to cognitive functions along with its maturation progressively.


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perception, emotion, neurocognition, communication, and sleep(Larson et al., 2010). Individuals who later fulfilled diagnosticcriteria for schizophrenia had shown significant premorbiddeficits in intellectual, language, and behavioral abilities atthe ages of 16–17 (Reichenberg et al., 2002). Symptoms such asproblems of language and cognitive development in children(3–11 years old) can predict schizophreniform disorder in adults(Cannon et al., 2002). From these results, it is presumed thatdisturbances of hippocampus and related brain regions play acentral role in prodromal symptoms of schizophrenia.Schizophrenia patients show hyperactivation of the amyg-

dala and underconnectivity of the VMPFC-amygdala pathway(Fan et al., 2013; Pankow et al., 2013). Therefore, it is probablethat in schizophrenia, like ASD, increased activity in theamygdala caused by hippocampal hyperactivation inducesdesensitization and dysregulation of the VMPFC. Theseimpairments of the VMPFC presumably lead to disturbancesof emotional responses in prodromal period of schizophrenia.Dysfunction of the Thalamus, Temporal Cortex, and

Prefrontal Cortex. There is neuronal connectivity betweenthe hippocampus and thalamus (Aggleton et al., 2010). Thethalamus is one of the damaged brain regions in at-risk mentalstate individuals and schizophrenia patients (Borgwardt et al.,2007; Chan et al., 2011). Schizophrenia patients with thalamicdysfunction show spindle range deficits that may probablycontribute to cognitive impairments (Ferrarelli et al., 2010;Wilson and Argyropoulos, 2012). In contrast, in healthysubjects, the fronto-temporal (VLPFC-STS/STG) connectionsreach 90% development in adulthood (Lebel et al., 2008),implying that immaturity of this pathway can prevent braindevelopment in adolescence. Therefore, it is presumed thatabnormalities of the thalamus caused by hippocampal hyper-activity can be exacerbated under immaturity of the fronto-temporal connections during late adolescence and early adulthoodin schizophrenia. These disturbances can induce STS/STG de-sensitization and VLPFC dysfunction, thereby leading to distur-bances of DLPFC top-down control (Fig. 2; Table 2).

Cuprizone-Treated Mice as an Animal Model ofPsychiatric Disorders

The treatmentwith cuprizone [bis(cyclohexylidenehydrazide)],the copper chelator, severely alters copper and zinc homeo-stasis in various tissues, including the CNS, and induces

demyelination in white and gray matters, such as the corpuscallosum, cerebral cortex, hippocampus, and cerebellum inmice (Zatta et al., 2005; Groebe et al., 2009; Gudi et al.,2009; Koutsoudaki et al., 2009). The treatment of cuprizone inmice is thought to be useful as a model of prion infectionbecause of the involvement of metal homeostasis in functionsof a cellular prion protein (PrPC) (Martins et al., 2001). PrPCis predominately expressed in neuronal cells (Ramasamyet al., 2003) and can bind copper, zinc, iron, and manganese(Brazier et al., 2008; Davies et al., 2009). Interestingly,manganese can induce prion protein transformation fromPrPC to a disease-associated isoform (PrPSc) (Brazier et al.,2008). Furthermore, PrPC but not PrPSc has SOD-1 activity,

TABLE 2Brain regions involved in social cognitive functions

Brain Regions Social Cognitive Functions

Prefrontal cortexDLPFCa Top-down control of social behaviorVLPFCb Integration of verbal and nonverbal informationVMPFCc Regulation for emotional responses

STS/STGd Integration of auditory and visual perceptionThalamuse Sensory gate for auditory and visual stimuliHippocampusf Emotion-associated memory, neurocognitionAmygdalaf Emotional responsesCerebellumg Cognition (early childhood), body and limb movement

aHeatherton and Wagner, 2011.bLevy and Wagner, 2011.cMotzkin et al., 2015.dKreifelts et al., 2007.eGeyer and Vollenweider, 2008.fOrsini and Maren, 2012.gWang et al., 2014.

Fig. 3. Neuroinflammation in cuprizone-treated mice. The treatmentwith cuprizone, the copper chelator, appears to disrupt cellular metalhomeostasis and presumably cause dysfunction of CuZn SOD-1 expressedin tanycytes in the BCB and/or in astrocytes in the BBB. Finally, thedysfunction of CuZn SOD-1 can induce neuroinflammation via reactiveoxygen species release, M1 polarization of macrophages/microglia, andproduction of proinflammatory cytokines, including tumor necrosis factor-a, IL-1b, CXCL10, CCL2, CCL3, CCL4, and CCL5.


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indicating a high oxidation potential of PrPSc (Brown et al.,1999; Milhavet et al., 2000; Yamamoto and Kuwata, 2009).Therefore, the lacking of SOD-1 activity in PrPSc seems to beassociated with reactive oxygen species production and neuro-inflammation under impaired cellular metal homeostasis.InC57BL/6mice treatedwith cuprizone, themRNA levels of

CCL2, CCL5, and CXC-chemokine ligand 10 (CXCL10), alter-natively termed IFN-g–inducible protein 10, showed thegreatest expression in the brain at 1–2 weeks of treatment,whereas CCL3, CCL4, tumor necrosis factor-a, and IL-1bincreased later (4–5 weeks) (McMahon et al., 2001). Further-more, activation of microglia and infiltration of macrophagesinto the brain are markedly increased during cuprizoneintoxication (McMahon et al., 2002). Recently, it has beenreported that microglial activation is significantly reduced inCXCL10-deficient mice treated with cuprizone, suggesting apivotal role of CXCL10 in cuprizone-induced neuroinflamma-tion and demyelination (Clarner et al., 2015). Similarly,IFN-g, IL-6, IL-8, CCL4, and CXCL10 were shown to besignificantly increased in the CSF of ASD individuals (Vargaset al., 2005). Consequently, impaired cellular metal homeo-stasis appears to induce neuroinflammation and demyelin-ation mediated by M1 phenotype of macrophage/microglia incuprizone-treated mice (Fig. 3).

Pharmacological Approach toNeuroinflammation in ASD and SchizophreniaBecause microglia-mediated neuroinflammation plays an

important role in schizophrenia and ASD, a drug that sup-presses microglial activation may be preferentially useful forthe therapy of these disorders. One of such candidates isminocycline, which inhibits the polarization of proinflamma-tory M1 microglia (Kobayashi et al., 2013; Pusic et al., 2014).Minocycline is a second-generation tetracycline and has beenin therapeutic use for over 30 years because of its antibioticproperties; however, it has been recently shown to exert avariety of biologic actions that are independent of theirantimicrobial activity, including anti-inflammatory and anti-apoptotic activities (Garrido-Mesa et al., 2013).Administration of minocycline attenuated the induction

of M1 microglia markers and inhibited the upregulation ofnuclear factor-kB, whereas it did not affect the expression ofM2 microglia markers in cultured microglia stimulated withlipopolysaccharide and in the spinal cord of SOD-1(G93A)mice (Kobayashi et al., 2013). In cuprizone-fed C57BL/6 mice,minocycline reduced microglial activation and demyelinationin the brain and prevented disturbances inmotor coordination(Pasquini et al., 2007; Skripuletz et al., 2010; Tanaka et al.,2013). Furthermore, minocycline in combination with anantipsychotic such as risperidone, olanzapine, quetiapine, orclozapine significantly improved positive, negative, and cog-nitive symptoms in recent-onset or chronic schizophreniapatients (Levkovitz et al., 2010; Ghanizadeh et al., 2014;Chaves et al., 2015; Kelly et al., 2015). From these results, it islikely that application of minocycline can dampen M1 signal-ing, subsequently resulting in skewing of M2a microglia thatreduce proinflammatory signaling and increase productionof anti-inflammatory cytokines. Consequently, minocyclineadd-on treatment may ameliorate clinical deterioration andbrain alterations in schizophrenia patients.

Although there is no clinical use of minocycline in ASD,recent studies have revealed improvement of ASD symptomsby intranasal administration of oxytocin and demonstratedthe association of polymorphisms in the oxytocin receptor(OXTR) gene in ASD (Andari et al., 2010; Guastella et al.,2010; Aoki et al.; 2014; LoParo and Waldman, 2015). Further-more, abnormal activation of microglia and a reduction ofPSD-95 expression in theOxtr-deficient brain (Miyazaki et al.,2016) have been found. Prenatal minocycline treatment canalter the expression of PSD-95 and ameliorate abnormalmother-infant communication in Oxtr-deficient mice (Miyazakiet al., 2016). These findings suggest that minocycline hasa therapeutic potential for the development of oxytocin/Oxtr-mediated ASD-like phenotypes.

ConclusionIn this review, we compare brain alterations in ASD and

those in schizophrenia and propose a possible mechanismunderlying social cognitive deficits. Development of ASDappearsto be triggered by cerebellar dysfunction and subsequentthalamic hyperactivation in early childhood. In contrast, schizo-phrenia seems to be induced by thalamic hyperactivation in lateadolescence, whereas hippocampal aberration possibly has beeninitiated in childhood. The thalamic hyperactivation can lead todysfunction of the DLPFC, which regulates neural circuitry ofsocial cognition. Consequently, we conclude that in ASD andschizophrenia, the initiating brain regions with abnormalitiesare distinct; however, the aberration of the same brain regioncontributes to social cognitive deficits, a common symptom.Furthermore, we strongly suggest that one of the primaryculprits is a disturbance inmetal homeostasis, which can inducedysfunction of the BCB rather than BBB. It is probable thatdysfunction of CuZn SOD-1 expressed in the BCB leads toneuroinflammation via reactive oxygen species release, M1polarization of macrophages/microglia, and production of proin-flammatory cytokines. M1 microglia-mediated neuroinflamma-tion appears to be associatedwith abnormalities of the initiatingbrain regions located adjacent to the cerebral ventricles andsubsequent dysregulation of the neural circuitry of socialcognition in the DLPFC. Consequently, a drug that selectivelysuppresses polarization ofM1microgliamayprovide a beneficialtherapy for ASD and schizophrenia. From this point of view,cuprizone-treated mice are thought to be a useful model formetal homeostasis disturbance and neuroinflammation inthese disorders. This view may pave the way for treatmentof ASD and schizophrenia.

Acknowledgments

The authors acknowledge Professor Sam J. Enna (University ofKansasMedical Center, Kansas City, KS) for invaluable comments onan early draft of this paper.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Nakagawa,Chiba.

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Address correspondence to: Dr. Yutaka Nakagawa, Innovative ResearchDivision, Mitsubishi Tanabe Pharma, Yokohama 227-0033, Japan. E-mail:[email protected]


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Involvement of Neuroinflammation during Brain Development ...jpet.aspetjournals.org/content/jpet/358/3/504.full.pdfthecerebellum,midbrain,fusiformgyrus,andprefrontalcortex in ASD adults