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Involvement of neuroinflammation during brain development in social cognitive deficits
in autism spectrum disorder and schizophrenia
Yutaka Nakagawa, Kenji Chiba
Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama
227-0033, Japan (Y. N., K. C.)
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Running title: Neuroinflammation in social cognitive deficits
Address correspondence to: Dr. Yutaka Nakagawa, Innovative Research Division,
Mitsubishi Tanabe Pharma Corporation, Yokohama 227-0033, Japan
Tel: +81-45-963-4744, fax: +81-45-963-4641,
E-mail: [email protected]
The number of tables: 2
The number of figures: 3
The number of references: 196
The number of words in the Abstract: 215
The number of words in the Introduction: 508
The number of words in the text: 5989
A list of nonstandard abbreviations used in the paper
ASD, autism spectrum disorder; BBB, blood-brain barrier; BCB, blood-cerebrospinal
fluid barrier; CCL, CC-chemokine ligand; CNS, central nervous systems; CNTNAP2,
contactin-associated
protein-like
2;
[11C](R)-PK11195,
[11C]
(R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3- isoquinoline carboxamide);
CSF, cerebrospinal fluid; CVOs, circumventricular organs; CXCL, CXC-chemokine
ligand; DLPFC, dorsolateral prefrontal cortex; FFA, fusiform face area; FOXP2,
forkhead box P2; IFN-γ, interferon-γ; IL, interleukin; PSD-95, postsynaptic density
protein 95; PrPC, cellular prion protein; PrPSc, a disease-associated isoform of the
prion protein; SOD-1, superoxide dismutase-1; STS, superior temporal sulcus; STG,
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The number of text pages: 22
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superior temporal gyrus; VLPFC, ventrolateral prefrontal cortex; VMPFC, ventromedial
prefrontal cortex.
Recommended section: Minireviews
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Abstract
Development of social cognition, a unique and high-order function, depends on brain
maturation from childhood to adulthood in humans.
Autism spectrum disorder (ASD)
and schizophrenia have similar social cognitive deficits while age of onset in each
disorder is different.
Pathogenesis of these disorders is complex and contains several
features including genetic risk factors, environmental risk factors, and sites of
abnormalities in the brain. Although several hypotheses have been postulated, they
these disorders develop at distinct developmental stages.
Development of ASD
appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation
in early childhood. By contrast, schizophrenia seems to be triggered by thalamic
hyperactivation in late adolescence while hippocampal aberration has been possibly
initiated in childhood.
One of the possible culprits is metal homeostasis disturbances
that can induce dysfunction of blood-cerebrospinal fluid barrier.
Thalamic
hyperactivation is thought to be induced by microglia-mediated neuroinflammation and
abnormalities of intracerebral environment. Consequently, it is likely that the thalamic
hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower
brain regions related to social cognition.
In this review, we summarize the brain
aberration in ASD and schizophrenia and provide a possible mechanism underlying
social cognitive deficits in these disorders based on their distinct ages of onset.
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seem to be insufficient to explain how brain alterations associated with symptoms in
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Introduction
Microglial cells contribute to immune-surveillance in the central nervous systems
(CNS) and polarization of microglial subsets (M1 and M2) plays an important role in
controlling the balance between promotion and suppression in neuroinflammation
(Ransohoff and Perry, 2009; Kettenmann et al., 2011; Mikita et al., 2011; Saijo and
Glass, 2011). M1 microglial cells can promote neuroinflammation and subsequent
neural network dysfunction in the CNS, whereas M2 microglia are implicated in
and Martinez, 2010). As we reported previously, imbalance of M1 and M2 microglia
appears to be closely related to mood aberration of major depressive disorder and
bipolar disorder (Nakagawa and Chiba, 2014, 2015).
Autism spectrum disorder (ASD)
is defined by deficits in social communication interaction and behavioral flexibility,
manifesting in early childhood (Volkmar et al., 2014).
Eighteen surveys conducted
according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition
(DSM-IV) criteria demonstrated that estimates of the rate of ASD range from 10 in
10,000 to 16 in 10,000, while the most recent study estimated the prevalence in the
United States as 11.3 in 1,000, suggesting that the prevalence of ASD is increasing
(Volkmar et al., 2014).
Parents of children with ASD have often reported that the first
sign of a problem with their child was the delay of language in the second year of life
(Tager-Flusberg, 2000).
Social cognitive deficits are a hallmark characteristic 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 and it develops in late adolescence most
frequently (Stahl, 2013). It is postulated that dopamine hyperactivity in the nucleus
accumbens (NAc) induced by hypofunction of glutamate receptors in the prefrontal
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inhibiting inflammation and restoring homeostasis (Mosser and Edwards, 2008; Gordon
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cortex and hippocampus is related to positive symptoms, while hypoactivation of
dopamine and glutamate neurons in the prefrontal cortex contributes to negative
symptoms (Stahl, 2013).
On the other hand, according to the neurodevelopmental
hypothesis, the etiology of schizophrenia appears to involve pathologic processes which
are caused by genetic and environmental risk factors and begin before the brain fully
matures (Weinberger, 1986; Marenco and Weinberger, 2000).
Pathogenesis of these disorders is complex and contains several features including
(Hultman et al., 1999; Gardener et al., 2011; Miles, 2011; Onore et al., 2012).
Recently, Meyer and colleagues, focusing on similarities and differences between
schizophrenia and ASD, implied that disturbed neurodevelopment by maternal infection
and succeeding prenatal neuroinflammation is shared by ASD and schizophrenia,
whereas persistent and latent neuroinflammation contributes to onsets of autism and
schizophrenia, respectively (Meyer et al., 2011a).
However, these hypotheses seem
not to clarify how brain alterations associated with symptoms in these disorders develop
at distinct developmental stages.
Therefore, in this article, we summarize the brain
aberration and related neuroinflammation in early and chronic phases of ASD, discuss
similarities and differences between social cognitive deficits in ASD and those in
schizophrenia, and provide a possible mechanism underlying the social cognitive
deficits in these disorders.
ASD and neuroinflammation
Genetic risk factors. While there has been considerable debate in etiology of
ASD, the genetic basis of this disorder is supported by several twin studies (Rosenberg
et al., 2009; Frazier et al., 2014). Much attention has been focused on a relationship
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genetic risk factors, environmental risk factors, and sites of abnormalities in the brain
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between ASD and a transcriptional gene, forkhead box P2 (FOXP2) which is closely
related to language ability (Bowers and Konopka, 2012). FOXP2 protein regulates
gene expression of MET (Mukamel, et al., 2011) and contactin-associated protein-like 2
(CNTNAP2) (Arking et al., 2008; Bowers and Konopka, 2012).
During gestation,
MET gene is selectively expressed in the temporal and occipital lobes which contribute
to verbal communication, implying that MET plays an important role in development of
language ability (Mukamel et al., 2011).
The CNTNAP2 encodes a cell adhesion
developing human brain (Arking et al., 2008). It has been reported that common
variants in CNTNAP2 are associated with several allied neurodevelopmental disorders
including ASD (Scott-Van Zeeland et al., 2010). Foxp2 mutant mice show ASD-Like
phenotypes such as reduced or atypical vocalizations and impairments of learning
performances (Shu et al., 2005; Fujita et al., 2008; Kurt et al., 2012).
Other studies demonstrated that ASD symptoms are associated with gene variations
of neuroligin (NLGN), neurexin (NRXN), SH3 and multiple ankyrin repeat domain 3
(SHANK3), and cell adhesion molecule 1 (CADM1) (Zhiling et al., 2008; Bourgeron,
2009; Fujita-Jimbo et al., 2015).
The variations of these synaptic cell adhesion
molecules seem to induce an imbalance of excitatory and inhibitory receptors and
synaptic pruning deficits (Lisé and El-Husseini, 2006; LeBlanc and Fagiolini, 2011).
In the process of synaptic pruning, up-regulation of myocyte enhancer factor 2 (MEF2)
can lead to ubiquitination of postsynaptic density protein 95 (PSD-95) in the
postsynaptic density and subsequently the degradation of ubiquitinated PSD-95 results
in a synapse elimination (Caroni et al., 2014).
Interestingly, mutated NLGN3 or
CADM1 protein up-regulates C/EBP-homologous protein (CHOP), a marker of
endoplasmic reticulum (ER) stress, suggesting that the synaptic pruning deficits induce
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molecule of neurexin subfamily and is highly expressed in frontal lobe circuits in
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ER stress and neuroinflammation in ASD (Fujita et al, 2010; Fujita-Jimbo et al., 2012,
2015). Consequently, these genetic factors presumably influence function of “neural
circuitry of social cognition” in combination with environmental risk factors.
Environmental risk factors.
Air pollutants, pesticides, polychlorinated
biphenyls, solvents, and glyphosate appear to be associated with development of ASD
(Sealey et al., 2016).
A possible relationship is shown between ASD severity and
blood or hair levels of heavy metals including mercury and lead (Rossignol et al., 2014).
brain antigens such as cypin which, along with PSD-95, can regulate dendritic
branching of hippocampal neurons (Braunschweig et al., 2013). Sodium valproate, an
anti-convulsant and a mood stabilizer, induces fetal neurodevelopment aberration in
animals including humans, higher incidence of ASD in humans, and ASD-like
phenotypes such as reduced social interaction and increased repetitive behaviors in
rodents (Roullet et al., 2013).
There are many prenatal and postnatal risk factors;
maternal medication use, C-reactive protein (CRP) levels, hypertension, hemorrhage,
infection, depressive symptomatology, and food, gestational diabetes, parental age at
birth, prolonged labor, fetal distress, birth injury or trauma, multiple birth, low birth
weight, and etc. (Glasson et al., 2004; Gardener et al., 2009, 2011; Lupien et al., 2011;
Patterson, 2011; Guinchat et al., 2012; Neggers, 2014; Xiang et al., 2015).
Metal homeostasis disturbances.
It is highly probable that a well balanced diet
plays an essential role in development and maintenance of brain functions, because
good nutrition is a cornerstone of good health, while poor nutrition is associated with
reduced immunity, impaired physical development, and reduced productivity (World
Health Organization, 2016). Children with ASD often have restricted diets which can
lead to nutrient deficiencies with brain metal homeostasis disturbances (Bilgiç et al.,
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A recent study revealed that some of ASD may be caused by maternal antibodies to fetal
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2010; Sidrak et al., 2014).
Iron deficiency is one of the most prevalent malnutrition,
affecting probable two billion people in the world, and pregnant women and young
children are affected most severely, because pregnancy and infant growth demand iron
(World Health Organization, 2016). Iron is required for basic cellular functions in all
the tissues, especially in the brain and muscle, and is critically important for the
oxygen-carrier function of hemoglobin in red blood cells (Breymann, 2015). In the
brain, iron is transported by transferrin or divalent metal transporter-1 (DMT-1) from
myelination process and monoamine neurotransmitter synthesis (Dusek et al., 2015).
Iron deficiency is suggested to be related to development of ASD (Bilgiç et al., 2010;
Sidrak et al., 2014). Lower iron concentrations in the blood appear to induce transport
of neurotoxic manganese instead of iron into the brain (Gunter et al., 2013; Dusek et al.,
2015).
When zinc levels are decreased and conversely copper levels are increased in the
blood during pregnancy, prevention of fetal development would be introduced (Faber et
al., 2009).
The imbalance of zinc and copper levels may deteriorate FOXP2 functions
and induce language disability, because FOXP2 contains zinc finger domain (Bowers
and Konopka, 2012).
Indeed, it has been reported that ASD children show reduced
zinc levels in their hairs and low blood zinc/copper ratio (Faber et al., 2009; Yasuda et al,
2011, 2013). Taken together, it is possible that metal homeostasis disturbances are one
of 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 microglia
cells with positron emission tomography (PET) (Banati, 2002).
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the peripheral blood and is essential for the activity of several enzymes involved in
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that [11C](R)-PK11195 binding potential values are significantly higher in the brain
regions including the cerebellum, midbrain, fusiform gyrus, and prefrontal cortex in
ASD adults as compared with controls (Suzuki et al., 2013). In the visual cortex in
autopsy brains, microglial densities are significantly greater in individuals with ASD
versus controls (Tetreault et al., 2012).
An immunohistochemical study revealed that a
marked activation of microglia and astrocytes in the middle frontal and anterior
cingulate gyri and cerebellum is obtained at autopsy from ASD subjects (Vargas et al.,
Similarly, microglial cells are markedly activated in the dorsolateral prefrontal
cortex (DLPFC) of ASD individuals (Morgan et al., 2010).
Risperidone in
combination with a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, showed a superior
efficacy as compared with monotherapy of risperidone in a randomized double-blind
placebo-controlled clinical study in ASD children (Asadabadi et al., 2013).
From these
results, neuroinflammation mediated by M1 microglia appears to be associated with
ASD.
Postmortem studies revealed prominent microglia activation and increased
pro-inflammatory cytokines and chemokines including IFN-γ, interleukin (IL)-1β, IL-6,
IL-12p40, tumor necrosis factor (TNF)-α, and CC-chemokine ligand 2 (CCL2) in the
brain, particularly in the frontal cortex, cerebellum, and cerebral spinal fluid (CSF) of
ASD individuals (Vargas et al., 2005; Li et al., 2009; Morgan et al., 2010; Onore et al.,
2012).
Similarly, the levels of IL-1β, IL-6, IL-8, IL-12p40, CCL2, CCL5, and CCL11
are significantly increased in the plasma of ASD individuals (Ashwood et al., 2011a, b).
The increased cytokine levels were predominantly in children who had a regressive
form of ASD and were associated with more impaired communication and aberrant
behaviors (Ashwood et al., 2011a, b).
Furthermore, BTBR T1tf/J mice with gene
mutation in kynurenine 3-hydroxylase (Kmo) related to neuroprotective actions show
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2005).
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elevated levels of pro-inflammatory cytokines including IL-1β and IL-6 in the
cerebellum and ASD-like phenotypes such as reduced social interactions and impaired
juvenile play (McFarlane et al., 2008; Heo et al., 2011).
On the other hand, the levels
of IL-4 and IL-10 in the plasma showed no difference between ASD and control
subjects (Ashwood et al., 2011b). The levels of transforming growth factor (TGF)-β in
ASD blood are significantly lower as compared with typically developing controls and
are negatively correlated with psychological symptom severity (Okada et al., 2007;
Therefore, it is highly possible that neuroinflammation mediated by M1 microglia
is associated with symptoms of ASD based on imbalance of pro-inflammatory M1 and
anti-inflammatory M2 polarization states of microglia.
Our view is on the lines of
previous hypotheses that the imbalance of M1/M2 polarization of microglia is
implicated in neuroinflammation and disruption of excitatory versus inhibitory balance
in the brain of ASD (Gottfried et al., 2015; Koyama and Ikegaya, 2015).
Disturbances in the blood-brain barrier (BBB).
The BBB has a unique barrier
structure between the lumen of cerebral blood vessels and brain parenchyma.
The
endothelial cells have luminal tight junction and are surrounded by basement membrane
and the pericytes.
Around all these structures are the astrocytic end feet processes
from nearby astrocytes.
The interaction among vascular endothelial cells, pericytes,
and astrocytes plays an important role in maintenance of BBB functions (Abbott et al.,
2006; Bonkowski et al., 2011). It is possible that BBB dysfunction contributes to
major depressive disorder and schizophrenia (Shalev et al., 2009).
Maternal hyperglycemia and hypertension are often associated with activation of
inflammatory cells, inducing abnormalities in capillary endothelial cells of the brain
(Jackson, 2011).
In the inflamed capillaries, pro-inflammatory cytokines and
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Ashwood et al., 2008).
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mediators contribute to the polarization and recruitment of M1 macrophages (Jackson,
2011). At early phase, M1 macrophages appear to remove injured vascular endothelial
cells by phagocytosis (Jackson, 2011; Phillipson and Kubes, 2011); however under
insufficient M2 condition, M1 macrophages can probably induce prolonged
inflammation and destruction of BBB.
The BBB possesses manganese sensitivity
(Bornhorst et al., 2012), suggesting that disequilibrium of iron and manganese levels is
presumably associated with dysfunction of BBB directly.
Imbalance of zinc and
copper, zinc superoxide dismutase (CuZn SOD)-1 activity (Chen et al., 2006). Taken
together, it is likely that dysfunction of BBB is caused by multiple prenatal and
postnatal risk factors.
Since BBB function is immature at early developmental stages
(Saunders et al., 2014), cerebral neural cells in fetuses, infants, and young children are
presumably vulnerable to these factors. Therefore, it is possible that BBB disturbances
are related to ASD.
Disturbances in the blood-cerebrospinal fluid barrier (BCB).
The BCB lies
between the choroid plexus vessels in circumventricular organs (CVOs) and the CSF
(Choi and Kim, 2008; Benarroch, 2011; Lun et al., 2015).
The CVOs are found to be
located around the cerebral ventricles and the CVOs with BCB are characterized by lack
of BBB properties (Choi and Kim, 2008; Benarroch, 2011). In the BCB, tanycytes,
highly specialized ependymal cells, have tight junction and play regulatory roles in
interaction among the blood, brain parenchyma, and CSF (Benarroch, 2011; Langlet et
al., 2013).
Tanycytes contribute to monitoring the CSF composition (Sisó et al.,
2010; Benarroch, 2011) and these cells seem to be vulnerable to imbalance of zinc and
copper levels, because tanycytes express CuZn SOD-1 (Peluffo et al., 2005).
Furthermore, the BCB is thought to be a major route for manganese into the CSF,
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copper levels may contribute to dysfunction of astrocytes, because astrocytes express
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because the increased blood manganese levels can induce severer dysfunction of the
BCB rather than BBB (Bornhorst et al., 2012).
Therefore, it is highly probable that
maternal disturbances of cellular metal homeostasis predominantly induce dysfunction
of tanycytes in the BCB and subsequent neuroinflammation that triggers aberration of
neural network in fetuses, infants, and young children (Fig. 1).
Social cognitive deficits in ASD
make plans and regulate actions in social situations appropriately (Heatherton and
Wagner, 2011).
This unique cognitive function depends on brain maturation from
childhood to adulthood in humans (Lebel et al., 2008; Catts et al., 2013). Therefore, it
is likely that immaturity negatively impacts high-order cognition acquired at each
developmental stage.
Dysfunction of the cerebellum. Young children with ASD (2-4 years of age)
show a significant increase in cerebellar volume as compared with typically developing
children, while cerebellar volume of ASD schoolchildren and adolescents is similar to
or rather smaller than controls (Sparks et al., 2002; Allen, 2005; Anagnostou and Taylor,
2011).
A diffusion tensor imaging (DTI) study to investigate brain anatomical
connectivity indicated a significant increase in fractional anisotropy (FA), the deviation
from pure isotropic diffusion of water mobility, in the brain regions including
cerebellum of young children with ASD (1-6 years of age) (Weinstein et al., 2011). On
the other hand, FA in the cerebellum is decreased in ASD schoolchildren (6-12 years
old) (Brito et al., 2009). Serotonin transporter binding is reduced in several brain
regions including cerebellum of ASD adults (Nakamura et al., 2010). Furthermore,
[11C](R)-PK11195 binding values are significantly higher in the brain regions including
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Cognitive function such as self-regulation and social cognition enables humans to
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cerebellum of ASD adults as compared with those of controls (Suzuki et al., 2013).
From these results, it is possible that neuronal hyperactivation and neuroinflammation
occur in the cerebellum of young children with ASD, subsequently leading to reduction
of neuronal activity and atrophy with persistent neuroinflammation in the cerebellum of
ASD schoolchildren, adolescents, and adults.
The cerebellum is involved in body and limb movement, executive and cognitive
functions, and language ability (Koziol et al., 2014; Wang et al., 2014).
ASD
occurs in young children and is persistent over time (Lee and Bo, 2015).
Although
cerebellar lesions are unlikely to result in profound cognitive deficits in adults,
cerebellar abnormalities at earlier ages lead to more conspicuous cognitive and affective
changes, diagnosed as cerebellar cognitive-affective syndrome (Wang et al., 2014).
Cerebellar cognitive-affective syndrome is characterized by disturbances of executive
function, impaired spatial cognition, personality change, and linguistic difficulties
(Schmahmann and Sherman, 1998).
It has been hypothesized that the cerebellum
plays a pivotal role in cognition in young children within the critical period (2-4 years
of age) and contributes to body and limb movement at every developmental stage
(Wang et al., 2014).
Thus, one could speculate that cerebellar aberration in young
children is associated with initiation of social cognitive deficits in ASD.
As mentioned in above section, impaired cellular metal homeostasis can induce
disturbances of cerebral ventricles and contributes to functional or structural alterations
in the brain. Because the cerebellum is located adjacent to the fourth ventricle and the
cerebral ventricles are partly surrounded by the choroid plexus in young children (Su
and Young, 2011; Liddelow, 2015), impaired cellular metal homeostasis probably
induces hyperactivation of the cerebellum via dysfunction of choroid plexus and fourth
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individuals often show motor abnormalities consistent with cerebellar dysfunction that
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ventricle in young children with ASD.
Neuronal hyperactivation can trigger M1
polarization of microglia in the cerebellum, and then M1 microglial-mediated
neuroinflammation and neural network dysfunction may extend to the related tissues
under inhibition in the M2 state. Consequently, it is possible that imbalance between
M1 and M2 polarization of microglia plays an important role in the progression of ASD
(Nakagawa and Chiba, 2014, 2015).
It is unlikely that symptoms of ASD can be caused by abnormalities in a single
increase in cerebral ventricular volume are observed in ASD schoolchildren and
adolescents (McAlonan et al., 2005).
There are neuronal connections between the
cerebellum and other brain regions (Mazzola et al., 2013; Rogers et al., 2013; Koziol et
al., 2014).
To understand symptoms, initiation, and progression of ASD more
precisely, it is important to analyze the neuropathological relation between the
cerebellum and other brain regions.
Dysfunction of the thalamus.
Like the cerebellum, the amygdala and
hippocampus were enlarged in children with ASD as compared with control subjects,
whereas no differences were found in adolescent amygdala volumes (Sparks et al.,
2002; Schumann et al., 2004).
On the other hand, atrophy and reduction of serotonin
transporter binding in the thalamus were 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 found in the thalamus of ASD adults (Suzuki
et al., 2013).
From these results, it is presumed that in young children with ASD,
neuroinflammation is initially induced in the thalamus and subsequently persistent
neuroinflammation induces thalamic atrophy in schoolchildren, adolescent, and adults.
Because the thalamus neighbors the third ventricle, dysfunction of the thalamus in ASD
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brain region, because a significant reduction in total grey matter volume and a marked
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may be related to impaired cellular metal homeostasis 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 from peripheral organs are sent to the thalamus, and
then to the primary auditory or visual area in the cerebral cortex (Tamietto and de
Gelder, 2010; Hackett, 2015).
Functions of the thalamus are impaired in ASD
schoolchildren, adolescents, and adults (Hardan et al., 2008; Lai et al., 2010).
induced in a light or mild motor performance such as 20 finger taps for each hand in
ASD schoolchildren (Mostofsky et al., 2009).
On the other hand, ASD individuals
show significantly increased activity in the cerebellum relative to control subjects when
they perform a rather complex motor task, in which they hold a joystick and press a
button with the thumb according to instruction (Allen et al., 2004). From these results,
it is likely that, in ASD, neural network activities between the cerebellum and thalamus
are decreased at resting state, whereas this pathway is activated when a task is provided.
In daily life of ASD individuals, activities of the cerebellum and cerebellum-thalamus
pathway appear to be increased, because social communication is always necessary.
Aberration of verbal communication.
Underconnectivity in the thalamo-frontal
pathway is induced in ASD schoolchildren and adolescents (Cheon et al., 2011).
On
the other hand, functional overconnectivity between the thalamus and temporal lobe
occurs in ASD schoolchildren and adolescents, although underconnectivity is found for
other cortical regions (Nair et al., 2013). Therefore, it is possible that hyperactivation
of the thalamus-temporal lobe connections is due to thalamo-frontal underconnectivity,
and that dysconnectivity of these pathways is associated with ASD symptoms.
ASD adults fail to activate the superior temporal sulcus (STS)/superior temporal
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Significant decreases in cerebellar activity and cerebellum-thalamus connectivity are
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gyrus (STG) in response to human vocal sounds, whereas they show a normal activation
pattern in response to non-vocal sounds (Gervais et al., 2004). Underconnectivity is
induced between the STS/STG and dopaminergic reward pathway including the ventral
tegmental area and NAc in ASD schoolchildren (Abrams et al., 2013). These results
suggest that chronic hyperactivation of the thalamus-temporal lobe connections induces
desensitization of the STS/STG, and that underconnectivity of STS/STG-reward
pathway impairs the ability of ASD children to experience speech as a pleasurable
It is
possible that the definite reduction of STS/STG reactivity to human vocal sounds in
ASD is caused by disturbances of the prefrontal cortex which regulates functions of the
STS/STG and is implicated in social cognition.
There are neuronal connections between the STS/STG and ventrolateral prefrontal
cortex (VLPFC) that integrates social cognitive information (Takahashi et al., 2007;
Levy and Wagner, 2011; Lai et al., 2012).
Underconnectivity between the temporal
cortex and VLPFC occurs in adult ASD (Sato et al., 2012).
In addition, VLPFC
activity is significantly reduced in schoolchildren and adolescents with ASD relative to
controls during speech stimulation (Lai et al., 2012).
Accordingly, it is presumable
that in daily life of ASD children, cerebellar and thalamic hyperactivation induces
dysfunction of the STS/STG and VLPFC, leading to a failure to integrate verbal
information, which probably persists in adulthood.
Aberration of non-verbal communication.
The thalamus, fusiform face area
(FFA), STS/STG, and VLPFC also play a pivotal role in non-verbal communication
including facial expressions, gestures, eye contact, and body language (Redcay, 2008;
Sato et al., 2012). These visual signals from the thalamus are sent to the visual cortex
and FFA (Tamietto and de Gelder, 2010; Blank et al., 2011). Microglial activity is
17
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stimulus, subsequently leading to deterioration of language and social skills.
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increased in the visual cortex/FFA of ASD individuals (Tetreault et al., 2012; Suzuki et
al., 2013).
Therefore, it is probable that thalamic hyperactivation induces
microglia-mediated neuroinflammation 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).
plays
a
key
role
in
direct
structural
connections
between
The STS/STG
verbal-
non-verbal-recognition areas (Kreifelts et al., 2007; Blank et al., 2011).
and
Functional
adults in response to emotional stimuli (Sato et al., 2012; Khan et al., 2013).
Taken
together, we hypothesize that abnormalities of verbal and non-verbal communication in
ASD are due to cerebellar and thalamic hyperactivation and subsequent dysfunction of
the visual cortex, FAA, STS/STG, and VLPFC.
Hippocampus-amygdala
interaction
and
emotional
responses.
The
hippocampus is thought to be vulnerable to developmental aberration during prenatal
stage (Abernethy et al., 2002; Beauchamp et al., 2008).
BCB abnormalities
accompanying with impaired cellular metal homeostasis may be related to hippocampal
dysfunction because of neighboring the hippocampus and lateral ventricle
(Dziegielewska et al., 2001; Kiernan, 2012).
The reciprocal interaction between amygdala and hippocampus contributes to
emotion, emotion-related memory, and neurocognition, and etc. (Potschka et al., 2011;
Orsini and Maren, 2012).
Hyperactivation of the amygdala occurs in ASD adults
during identification of previously viewed faces (Kleinhans et al., 2008; Monk et al.,
2010; Dichter, 2012).
Social impairment is positively correlated to amygdala
activation but is negatively related to amygdala-FFA connectivity in ASD (Kleinhans et
al., 2008; Dichter, 2012).
Development of face perception and social cognitive skills is
18
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underconnectivity between the visual cortex and STS/STG or VLPFC occurs in ASD
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supported by the amygdala-FFA system (Schultz, 2005; Vuilleumier and Pourtois, 2007).
Therefore, underconnectivity of amygdala-FFA pathway in ASD appears to induce
overconnectivity between the amygdala and brain regions other than FFA.
The ventromedial prefrontal cortex (VMPFC) plays a critical role in regulation of
amygdala activity (Blair, 2013; Motzkin et al., 2015).
ASD subjects show increased
neuronal activities in the VMPFC and amygdala in response to emotional stimuli and
higher microglial activity in the VMPFC (Monk et al., 2010; Suzuki et al, 2013).
Poor
suggesting lower VMPFC functions (Sawa et al., 2013). Accordingly, it is likely that
long-lasting hyperactivation of the amygdala induces VMPFC dysfunction which is
mediated by neuroinflammation.
The dysfunction of VMPFC probably causes
dysregulation between the VMPFC and amygdala and may 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 make an appropriate planning and action in social situations
based on integration of information including verbal and non-verbal cognition, working
memory, and evaluation of immediate as well as future outcomes (Tanaka et al., 2004;
Weissman et al., 2008; Heatherton and Wagner, 2011).
The number and size of neuron
are significantly increased in the DLPFC of ASD subjects (Courchesne et al., 2011).
Compared with typically developing subjects, ASD schoolchildren and adolescents
perform significantly worse on DLPFC task (Dawson et al., 1998; Sawa et al., 2013).
The ratio of N-acetyl-aspartate/creatine/phosphocreatine (NAA/Cr) in the DLPFC is
positively correlated with social ability scores in ASD children and adolescents (Fujii et
al., 2010). From these results, hypoactivation of the DLPFC appears to occur in ASD
like other psychiatric disorders (Hassel et al., 2008; Kang et al., 2012; Palaniyappan et
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performance on the Iowa gambling task is found in ASD schoolchildren and adolescents,
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al., 2013) and disturbances in top-down control of lower brain regions by DLPFC may
result in social cognitive deficits.
Taken together, we hypothesize that impaired cellular metal homeostasis, one of
primary culprits, can initially induce disturbances of the BCB rather than BBB and
subsequent cerebellar hyperactivation in young children with ASD.
The cerebellar
hyperactivation appears to increase thalamic activity and connectivity between the
thalamus and STS/STG because of underconnectivity of the thalamo-frontal pathway,
On the other hand,
hyperactivation of the hippocampus and amygdala probably causes dysregulation of
VMPFC responsible for emotional responses.
These events in childhood may induce
hypoactivation of the DLPFC which controls lower brain regions related to social ability,
and then leading to social cognitive deficits in ASD.
Social cognitive deficits in schizophrenia
The major clinical, biochemical, and genetic features in ASD and schizophrenia are
summarized in Table 1.
Although contribution of pathogenic genes are different in
these disorders, similar characteristics are seen in social cognitive deficits, disturbances
in glutamate, γ-aminobutyric acid (GABA), and dopamine neurotransmission, and
increasing pro-inflammatory responses.
Dysfunction of the hippocampus and amygdala.
Findings concerning
cerebellar aberration have been controversial in schizophrenia unlike ASD (Bottmer et
al., 2005).
In schizophrenia, cerebellar disturbances contribute to “neurological soft
signs” such as observable defects in sensory integration, motor coordination, and
behavioral inhibition, which are largely distinct from the core symptoms (Bottmer et al.,
2005; Chan et al., 2010; Shinn, et al., 2015).
20
Accordingly, it is unlikely that cerebellar
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thereby resulting in dysfunction of STS/STG and VLPFC.
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aberration is associated with cognitive deficits in schizophrenia.
Individuals with ARMS (At Risk Mental State) and patients with the first-episode
or chronic schizophrenia have lower volumes of several brain regions including the
hippocampus persistently (Borgwardt et al., 2007; Chan et al., 2011). In addition,
significantly reduced hippocampal volume with relatively higher plasma IL-6 levels is
induced in antipsychotic-naive schizophrenia patients with polymorphism IL-6 gene,
implying that hippocampal aberration caused by elevated IL-6 is neurodevelopmental
Similarly, higher IL-6 response by
maternal immune activation in prenatal stage is suggested to be associated with brain
alterations to initiate schizophrenia (Brown, 2011).
Therefore, the hippocampus
appears 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 perception, emotion, neurocognition,
communication, and sleep (Larson et al., 2010).
Individuals who later fulfilled
diagnostic criteria for schizophrenia had shown significant premorbid deficits in
intellectual, language, and behavioral abilities at the ages of 16-17 (Reichenberg et al.,
2002).
Symptoms such as problems 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 that disturbances of hippocampus and related
brain regions play a central role in prodromal symptoms of schizophrenia.
Schizophrenia
patients
show
hyperactivation
of
the
amygdala
and
underconnectivity of the VMPFC-amygdala pathway (Fan et al., 2013; Pankow et al.,
2013).
Therefore, it is probable that in schizophrenia, like ASD, increased activity in
the amygdala caused by hippocampal hyperactivation induces desensitization and
dysregulation of the VMPFC.
These impairments of the VMPFC presumably lead to
21
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origin of schizophrenia (Kalmady et al., 2014).
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disturbances of emotional responses in prodromal period of schizophrenia.
Dysfunction of the thalamus, temporal cortex, and prefrontal cortex.
There is
neuronal connectivity between the hippocampus and thalamus (Aggleton et al., 2010).
The thalamus is one of damaged brain regions in ARMS individuals and schizophrenia
patients (Borgwardt et al., 2007; Chan et al., 2011).
Schizophrenia patients with
thalamic dysfunction show spindle range deficits which may probably contribute to
cognitive impairments (Ferrarelli et al., 2010; Wilson and Argyropoulos, 2012).
On
reach 90% development in adulthood (Lebel et al., 2008), implying that immaturity of
this pathway can prevent brain development in adolescence. Therefore, it is presumed
that abnormalities of the thalamus caused by hippocampal hyperactivity can be
exacerbated under immaturity of the fronto-temporal connections during late
adolescence and early adulthood in schizophrenia.
These disturbances can induce
STS/STG desensitization and VLPFC dysfunction, thereby leading to disturbances of
DLPFC top-down control (Fig. 2 and Table 2).
Cuprizone-treated mice as an animal model of psychiatric disorders
The treatment with cuprizone [bis(cyclohexylidenehydrazide)], the copper chelator
severely alters copper and zinc homeostasis in various tissues including the CNS and
induces demyelination in white and gray matters such as the corpus callosum, cerebral
cortex, hippocampus, and cerebellum in mice (Zatta et al., 2005; Groebe et al., 2009;
Gudi et al., 2009; Koutsoudaki et al., 2009). The treatment of cuprizone in mice is
thought to be useful as a model of prion infection because of the involvement of metal
homeostasis in functions of a cellular prion protein (PrPC) (Martins et al., 2001).
PrPC is predominately expressed in neuronal cells (Ramasamy et al., 2003) and can
22
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the other hand, in healthy subjects, the fronto-temporal (VLPFC-STS/STG) connections
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bind copper, zinc, iron, and manganese (Brazier et al., 2008; Davies et al., 2009).
Interestingly, manganese can induce prion protein transformation from PrPC to a
disease-associated isoform (PrPSc) (Brazier et al., 2008).
Furthermore, PrPC but not
PrPSc has SOD-1 activity 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 be associated with reactive oxygen species (ROS)
production and neuroinflammation under impaired cellular metal homeostasis.
CXC-chemokine ligand 10 (CXCL10), alternatively termed IFN-γ-inducible protein 10
(IP10), showed the greatest expression in the brain at 1 to 2 weeks of treatment whereas
CCL3, CCL4, TNF-α, and IL-1β increased later (4-5 weeks) (McMahon et al., 2001).
Furthermore, activation of microglia and infiltration of macrophages into the brain are
markedly increased during cuprizone intoxication (McMahon et al., 2002).
Recently,
it has been reported that microglial activation is significantly reduced in
CXCL10-deficient mice treated with cuprizone, suggesting a pivotal role of CXCL10 in
cuprizone-induced neuroinflammation and demyelination (Clarner et al., 2015).
Similarly, IFN-γ, IL-6, IL-8, CCL4, and CXCL10 were shown to be significantly
increased in the CSF of ASD individuals (Vargas et al., 2005). Consequently, impaired
cellular metal homeostasis appears to induce neuroinflammation and demyelination
mediated by M1 phenotype of macrophage/microglia in cuprizone-treated mice (Fig. 3).
Pharmacological approach to neuroinflammation in ASD and schizophrenia
Because microglia-mediated neuroinflammation plays an important role in
schizophrenia and ASD, a drug that suppresses microglial activation may be
preferentially useful for the therapy of these disorders.
23
One of such candidates is
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In C57BL/6 mice treated with cuprizone, the mRNA levels of CCL2, CCL5, and
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minocycline that inhibits the polarization of pro-inflammatory M1 microglia
(Kobayashi et al., 2013; Pusic et al., 2014).
Minocycline is a second-generation
tetracycline and has been in therapeutic use for over 30 years because of its antibiotic
properties; however, it has been recently shown to exert variety of biological actions
that are independent of their anti-microbial activity, including anti-inflammatory and
anti-apoptotic activities (Garrido-Mesa, 2013).
Administration of minocycline attenuated the induction of M1 microglia markers
expression of M2 microglia markers in cultured microglia stimulated with
lipopolysaccharide (LPS) 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 demyelination in the brain, and prevented disturbances in motor coordination
(Pasquini et al., 2007; Skripuletz et al., 2010; Tanaka et al., 2013). Furthermore,
minocycline in combination with an antipsychotic such as risperidone, olanzapine,
quetiapine, or clozapine significantly improved positive, negative and cognitive
symptoms in recent-onset or chronic schizophrenia patients (Levkovitz et al. 2010;
Chaves et al., 2015; Ghanizadeh et al. 2014; Kelly et al, 2015).
From these results, it
is likely that application of minocycline can dampen M1 signaling, subsequently
resulting in skewing of M2a microglia that reduce pro-inflammatory signaling and
increase production of anti-inflammatory cytokines.
Consequently, minocycline
add-on treatment may ameliorate clinical deterioration and brain alterations in
schizophrenia patients.
While there is no clinical use of minocycline in ASD, recent studies have revealed
improvement of ASD symptoms by intranasal administration of oxytocin and
demonstrated the association of polymorphisms in the oxytocin receptor (OXTR) gene
24
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and inhibited the up-regulation of nuclear factor (NF)-κB, whereas it did not affect the
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in ASD (Andari et al., 2010; Guastella et al., 2010; Aoki et al; 2014; LoParo and
Waldman, 2015). Furthermore, it has been found that abnormal activation of microglia
and a reduction of PSD95 expression in the Oxtr-deficient brain (Miyazaki et al., 2016).
Prenatal minocycline treatment can alter the expression of PSD95 and ameliorate
abnormal mother-infant communication in Oxtr-deficient mice (Miyazaki et al., 2016).
These findings suggest that minocycline has a therapeutic potential for the development
of oxytocin/Oxtr-mediated ASD-like phenotypes.
In this review, we compare brain alterations in ASD and those in schizophrenia and
propose a possible mechanism underlying social cognitive deficits.
Development of
ASD appears to be triggered by cerebellar dysfunction and subsequent thalamic
hyperactivation in early childhood.
On the other hand, schizophrenia seems to be
induced by thalamic hyperactivation in late adolescence, while hippocampal aberration
possibly has been initiated in childhood.
The thalamic hyperactivation can lead to
dysfunction of the DLPFC which regulates neural circuitry of social cognition.
Consequently, we conclude that in ASD and schizophrenia, the initiating brain regions
with abnormalities are distinct; however the aberration of the same brain region
contributes to social cognitive deficits, a common symptom. Furthermore, we strongly
suggest that one of primary culprits is a disturbance in metal homeostasis, which can
induce dysfunction of the BCB rather than BBB. It is probable that dysfunction of
CuZn SOD-1 expressed in the BCB leads to neuroinflammation via ROS release, M1
polarization of macrophages/microglia, and production of pro-inflammatory cytokines.
M1 microglia-mediated neuroinflammation appears to be associated with abnormalities
of the initiating brain regions located adjacent to the cerebral ventricles and subsequent
25
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Conclusion
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dysregulation of the neural circuitry of social cognition in the DLPFC.
Consequently,
a drug that selectively suppresses polarization of M1 microglia may provide a beneficial
therapy for ASD and schizophrenia. From this point of view, cuprizone-treated mice
are thought to be a useful model for metal homeostasis disturbance and
neuroinflammation in these disorders.
This view may pave the way for treatment of
ASD and schizophrenia.
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26
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Acknowledgements
The authors would like to acknowledge Professor Sam J. Enna (University of
Kansas Medical Center, U.S.A.) for invaluable comments on an early draft of this paper.
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27
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Authorship Contributions
Wrote or contributed to the writing of the manuscript: Nakagawa and Chiba.
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28
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Footnotes
The authors declare no conflict of interest.
Both authors are employees of
Mitsubishi Tanabe Pharma Corporation and have not received financial support from
any other institution.
The author to receive reprint requests: Dr. Yutaka Nakagawa, Innovative Research
Division, Mitsubishi Tanabe Pharma Corporation, Yokohama 227-0033, Japan
E-mail: [email protected]
Order of appearance is as follows, 1 Yutaka Nakagawa, 2 Kenji Chiba.
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Tel: +81-45-963-4744, fax: +81-45-963-4641,
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Legends for Figures
Fig. 1. The cerebral ventricles, blood-brain barrier, and blood CSF barrier.
(A) The
lateral, third, and fourth ventricles neighbor brain regions such as hippocampus,
amygdala, thalamus, and cerebellum.
(B) The BBB has a pivotal role in sufficient
supply of oxygen and nutrients to neurons and consists of the pericytes, end foot of
astrocytes, and vascular endothelial cells which have luminal tight junction.
(C) In the
BCB, tanycytes, highly specialized ependymal cells, have tight junction and play
tissues with BCB are characterized by lack of BBB properties.
Brain
Astrocytes and
tanycytes express CuZn SOD-1.
Fig. 2. A possible mechanism underlying social cognitive deficits in ASD and
schizophrenia on their distinct ages of onset. (A) Social cognitive functions develop
accompanying with human brain maturation from childhood to adulthood and are
related to increases in myelination of white matter tracts between the prefrontal cortex
and other brain regions.
(B) In ASD, impaired cellular metal homeostasis, one of
primary culprits, can induce dysfunction of the BCB rather than BBB, thereby leading
to cerebellar aberration and subsequent thalamic hyperactivation in childhood. In the
next step, the overconnectivity is induced between the thalamus and temporal lobe
(STS/STG) because of underconnectivity of the thalamo-frontal pathway.
thalamic
hyperactivation
is
thought
to
be
induced
by
The
microglia-mediated
neuroinflammation and presumably leads to dysfunction of the prefrontal cortex
including DLPFC which regulates functions of lower brain regions contributing to
social cognition.
In schizophrenia, on the other hand, hippocampal aberration can
occur in childhood and result in succeeding hyperactivation of the thalamus in late
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regulatory roles in interaction among the blood, brain parenchyma, and CSF.
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adolescence. The thalamic hyperactivation appears to be promoted due to immaturity
of the fronto-temporal pathway and finally lead to DLPFC dysfunction with a similarity
to ASD.
(C) The cerebellum and prefrontal cortex are involved differently in social
cognitive functions based on the maturation of the brain. The cerebellum appears to
play a predominant role in cognitive functions at young childhood because the
cerebellum has fully maturated at that time. On the other hand, the prefrontal cortex is
thought to contribute to cognitive functions along with its maturation progressively.
The treatment with cuprizone,
the copper chelator, appears to disrupt cellular metal homeostasis and presumably cause
dysfunction of CuZn SOD-1 expressed in tanycytes in the BCB and/or in astrocytes in
the BBB.
Finally, the dysfunction of CuZn SOD-1 can induce neuroinflammation via
ROS release, M1 polarization of macrophages/microglia, and production of
pro-inflammatory cytokines including TNF-α, IL-1β, CXCL10, CCL2, CCL3, CCL4,
and CCL5.
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Fig. 3. Neuroinflammation in cuprizone-treated mice.
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TABLE 1
Comparison 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 of
Biochemical
Disturbances
in
neurotransmission
glutamate,
GABA,
and
dopamine
c
. Increases in pro-inflammatory cytokine
(IL-1β, IL-6, TNF-α, IFN-γ) levels in the brain, CSF, and blood d.
No alterations in anti-inflammatory cytokine (IL-4, IL-10) levels
in the blood e.
Genetic
CNTNAP2, NLGN, NRXN, SHANK3, CADM1, etc. f.
Schizophrenia
Clinical
Positive, negative, cognitive symptoms (social cognitive deficits) g.
Develops in late adolescence most frequently g.
Biochemical
Disturbances
in
neurotransmission
glutamate,
GABA,
and
dopamine
g
. Increases in pro-inflammatory cytokine
(IL-1β, IL-6, TNF-α) 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.
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mind task b. Manifests in early childhood a.
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CSF, cerebrospinal fluid; GABA, γ-aminobutyric acid; IFN-γ, interferon-γ; IL,
interleukin; TNF-α, tumor necrosis factor-α.
CADM1, cell adhesion molecule 1; CNTNAP2, contactin-associated protein-like 2;
COMT, catechol-O-methyltransferase; DISC1; disrupted in schizophrenia 1; DRD2,
dopamine receptor D2; DTNBP1, dystrobrevin binding protein 1; HTR2A,
5-hydroxytryptamine (serotonin) receptor 2A; NLGN, neuroligin; NRG1, neuregulin 1;
NRXN, neurexin; SHANK3, SH3 and multiple ankyrin repeat domain 3.
Volkmar et al. (2014); b Pilowsky et al. (2000); c Money and Stanwood (2013); d
Onore et al. (2012); e Ashwood et al. (2011b); f Bourgeron (2009); g Stahl (2013); h
Meyer et al. (2011b); i Gejman et al. (2010).
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a
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TABLE 2
Brain regions involved in social cognitive functions.
Brain regions
Social cognitive functions
Prefrontal cortex
Top-down control of social behavior
VLPFC b
Integration of verbal and non-verbal information
VMPFC c
Regulation for emotional responses
STS/STG d
Integration of auditory and visual perception
Thalamus e
Sensory gate for auditory and visual stimuli
Hippocampus f
Emotion-associated memory, neurocognition
Amygdala f
Emotional responses
Cerebellum g
Cognition (early childhood), body and limb movement
DLPFC, dorsolateral prefrontal cortex; STG, superior temporal gyrus; STS, superior
temporal sulcus; VLPFC, ventrolateral prefrontal cortex; VMPFC, ventromedial
prefrontal cortex.
a
Heatherton and Wagner (2011); b Levy and Wagner (2011); c Motzkin et al. (2015); d
Kreifelts et al. (2007); e Geyer and Vollenweider (2008); f Orsini and Maren (2012); g
Wang et al. (2014).
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DLPFC a
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