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Neurosignals 2010;18:113–128
DOI: 10.1159/000319828
Maternal Immune Activation and Autism
Spectrum Disorder: Interleukin-6
Signaling as a Key Mechanistic Pathway
E.CarlaParker-Athill a–c JunTan a–c
a Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center,
b Department of Psychiatry
and Behavioral Medicine,
c College of Medicine, University of South Florida, Tampa, Fla. , USA
in these models in genes which regulate neurological and
immunological development, similar to what is observed
clin ically in ASD. Altogether, the role of MIA and cytokine
dysregulation, as a key mediator in the neuropathological,
behavioral and possibly genetic irregularities observed clin-
ically in autism are important factors that warrant further in-
vestigation. Copyright © 2010 S. Karger AG, Base l
Introduction
Originally adapted form the Greek ‘autos’ or ‘self’, the
term autism was first used in the early 1900s by Swiss
psychiatrist Eugen Bleuler to describe a cluster of symp-
toms in schizophrenic individuals which included with-
drawal or ‘self-isolation’ [1] . The term would later be used
by Kanner in the 1940s, to describe a similar group of
symptoms in children [1] . These early clinicians believed
autism and the manifestations of social withdrawal to be
the result of ‘cold’ unemotional parents. As a result, treat-
ments for autism centered on medications such as lysergic
acid diethylamide (LSD), electric shock and behavior
change techniques, which encompassed pain and pun-
ishment therapy. As the understanding of the disorder
Key Words
Autism spectrum disorder ⴢ Fetal immune response
syndrome ⴢ Maternal immune activation ⴢ Interleukin-6
Abstract
An emerging area of research in autism spectrum disorder
(ASD) is the role of prenatal exposure to inflammatory me-
diators during critical developmental periods. Epidemiolog-
ical data has highlighted this relationship showing signifi-
cant correlations between prenatal exposure to pathogens,
including influenza, and the occurrence of ASD. Although
there has not been a definitive molecular mechanism estab-
lished, researchers have begun to investigate this relation-
ship as animal models of maternal infection have support-
ed epidemiological findings. Several groups utilizing these
animal models have found that activation of the maternal
immune system, termed maternal immune activation (MIA),
and more specifically the exposure of the developing fetus
to maternal cytokines precipitate the neurological, immuno -
logical and behavioral abnormalities observed in the off-
spring of these animals. These abnormalities have correlated
with clinical findings of immune dysregulation, neurological
and behavioral abnormalities in some autistic individuals.
Additionally, researchers have observed genetic variations
Receive d: May 31, 2010
Accepted af ter revision: July 30, 2010
Publishe d online: October 2, 2010
Dr. Jun Tan
Department of Psychiatr y, Silver Ch ild Development Center
Universit y of South Florida, 3515 E. Fletc her Ave.
Tampa, FL 33613 (USA)
Tel. +1 813 974 9326, Fax +1 813 974 3223, E-Ma il jtan
@ health.usf.edu
© 2010 S. Karger AG, Basel
Accessible online at:
www.karger.com/nsg
Parker-Athill /Tan
Neurosignals 2010;18:113–128
114
evolved largely during the late 1990s, the role of behav-
ioral therapy centered on the use of highly controlled
learning environments, a form of therapy which has re-
mained a key feature of autism therapy today. With an
increased understanding of the disorder, clinicians began
to characterize key phenotypes to aid in the assessment
of individuals. With this came the inclusion of autism in
the Diagnostic and Statistical Manual of Mental Disorders
(DSM), as a behaviorally defined developmental disorder.
Today, the term autism is still used to describe the
cluster of symptoms manifested in children displaying
withdrawn or ‘isolated’ social behaviors, although clas-
sification and diagnostic criteria have evolved. Usually
diagnosed during the first 3 years, early autistic patients
often presented with a narrow range of symptoms, which
often included moderate-to-severe mental retardation,
although patients now present with symptoms that vary
in both severity and combination with almost 30% of per-
sons now having normal verbal expressions and IQ scores
[2, 3] . These changes in clinical observations have led to
the classification of autism as a spectrum disorder, autism
spectrum disorder (ASD), which describes a group of de-
velopmental disorders characterized by impairments in
reciprocal social interaction and verbal and nonverbal
communication skills compounded by symptoms of re-
strictive and repetitive behaviors and/or stereotyped pat-
terns of interest that are abnormal in their intensity or
focus [4–7] . Included in this spectrum is ‘classical’ au-
tism, which usually involves the stereotypical social isola-
tion, impaired verbal communication and repetitive be-
haviors; Asperger syndrome, often described as a milder
form of autism, lacking the components of intense repet-
itive behaviors and social withdrawal; and pervasive de-
velopmental disorder, which usually encompasses disor-
ders that cannot otherwise be classified [2, 7–9] .
These diagnostic changes in the clinical community,
coupled with increased education and awareness among
the clinical, research and general community, have also
led to important changes in the epidemiological study of
ASD. Previous epidemiological surveys, including those
conducted prior to the classification of autism as a spec-
trum disorder, often used strict diagnostic criteria which
resulted in the exclusion of individuals who would today
be classified as autistic. These changes have led to in-
creased research into the etiology of autism through the
establishment of autism registries and the utilization of
cohort studies. Although the exact etiology of the disor-
der has not been identified, potential environmental
‘triggers’, such as prenatal viral exposure, and genetic
vulnerabilities, including mutations and polymorphisms
in critical genes, have been among the epidemiological
findings [10, 11] . Additionally, these studies have provid-
ed important information for the scientific community,
which has begun to utilize animal models to investigate
the role of environmental insults, such as prenatal viral
exposure, in the etiology of autism. Several researchers
have had promising results in this area not only confirm-
ing the potential for prenatal viral exposure to induce ab-
errant behavioral outcomes in offspring, but also the
identification of the maternal cytokine response to viral
pathogens, referred to as maternal immune activation
(MIA) by Smith et al. [12] , as a possible mechanism in the
precipitation of these aberrant behaviors.
Despite this evidence, there is still disagreement with-
in the research community concerning the environmen-
tal etiology of autism. Nevertheless, epidemiological and
scientific observations supporting this role cannot be ig-
nored, leading several researchers to conclude that cer-
tain ‘environmental insults’ may act as triggers, precipi-
tating the development of autism. Furthermore, the lack
of a single gene candidate and the observed genetic diver-
sity w it hin the autistic population have also led research-
ers to theorize that in genetically vulnerable individuals,
environmental insults, such as prenatal viral exposure
and resulting MIA, may explain the diverse behavioral
phenotypes presented clinically in this spectrum disor-
der, as different genetic polymorphisms may differential-
ly precipitate certain behavioral outcomes.
Environmental Theory of ASD: Epidemiological
Perspective
Epidemiological studies have long been used in the
investigation of diseases and disorders to deduce their
etiology through the examination of trends, risk factors
and commonalities in affected populations. Their ap-
plication to neurodevelopmental disorders such as ASD
has however had several obstacles including small sam-
ple sizes and changes in diagnostic criteria and classifi-
cation systems. Early autism studies, for example, often
utilized Kanner’s autism criteria which employed strict
diagnostic criteria encompassing narrow phenotypic
ranges. The results were smaller sample sizes and lower
observations of prevalence [13] . Today, with increased
education and utilization of the DSM and the Interna-
tional Classification of Diseases criteria, researchers are
more aware of the various phenotypic presentations
seen within the autistic population, including more
atypical types of autism. As a result, today’s studies of-
Maternal Immune Activation and Autism
Spectrum Disorder
Neurosignals 2010;18:113–128
115
ten encompass larger sample populations allowing for
the collection of more statistically relevant data, al-
though they have also resulted in perceived higher rates
of prevalence than previous studies [7, 14–16] . In a com-
parative analysis by Kielinen et al. [17] , for example, the
Kanner and DSM criteria were used to assess the preva-
lence of autism within the same sample population,
wh ich reveale d an i ncrease in preva len ce w hen the DSM
criteria was used. As eluded to by Kielinen, these chang-
es in prevalence may be attributable to methodological
changes in these studies; changes in diagnostic, classifi-
cation and inclusion criteria; and increased awareness
and education among the clinical and general commu-
nities [17–19] . It is important to note that although an
upward trend in prevalence has been observed, consis-
tencies have remained in gender disparities as a higher
rate of autism is reported in males throughout these
studies [17, 20] .
Epidemiological Studies: Genetic Predictors of ASD
Although changes within the field of ASD research
have altered the way epidemiological surveys are con-
ducted making chronological analysis of prevalence dif-
ficult, they have allowed for increased utilization of preg-
nancy/birth cohorts and other registries previously un-
derutilized in the study of ASD. Additionally, dedicated
autism registries now provide not only diagnostic and
survey information, but often include biological speci-
mens, such as serum samples, which can be utilized for
biological assays and genetic analysis for commonalities
within this population as well as divergences from con-
trol populations – all necessary information for the elu-
cidation of the etiology of this disorder.
Genetic high-risk cohorts have been another resource
utilized to examine the role of genetics in the etiology of
ASD. These studies have differed from other areas, how-
ever, by utilizing sibling data rather than offspring.
Through these studies, the genetic component of ASD has
been shown as the recurrence rate in siblings, estimated at
3–8%, 60–90% for identical twins, show not only a strong
genetic component but also a potentially significant role
for epigenetic factors, including maternal inheritance and
imprinting. Despite these findings, there has not been a
‘single gene’ candidate discovered for ASD, although sev-
eral genes have been identified as abnormally expressed
or polymorphic at a higher rate within the autistic popu-
lation. Among these genes have been those involved in
neuronal and synaptic formation and function, including
reelin, neurogenin-1 and neuroligin-4, as well as those in-
volved in immune regulation, such as cytokine receptor
glycoprotein 130 (gp-130), although this gene product has
been shown to possess several biological functions [21–25] .
Epidemiological Studies: Environmental Predictors of
ASD
The genetic diversity within the autistic population, in
addition to the phenotypic variability observed clinically
has posed a significant obstacle in identifying the etiol-
ogy of ASD; however, it has led many researchers to ex-
amine alternative causative agents that may contribute to
the neuropathology of this disorder. Researchers have
now begun to utilize exposure-based high-risk cohorts,
which are used to examine the effects of environmental
risk factors on the etiology of disorders, to elucidate po-
tential environmental etiologies of ASD. These cohorts
not only examine environmental etiologies of disorders,
but also how these environmental factors can interact
with genes to precipitate these disorders, often creating
diverse phenotypic presentations within a given disorder
such as variations in symptom severity.
The utilization of these cohort studies, including the
exposure risk cohort design, in the field of schizophrenia
has identified several factors, including genetic polymor-
phisms and prenatal viral exposure, as significant risk
factors in the etiology of this disorder [26–30] . Similarly,
recent studies in ASD research, such as those examining
prenatal exposure to rubella and other viral agents, have
also alluded to a possible environmental etiology of ASD,
and several researchers have seen significant correlations
between prenatal exposure and the occurrence of this
disorder in offspring [31–33] . It is important to note, how-
ever, that there have been several studies, such as the in-
vestigation of intrauterine human parvovirus infection
by Anlar et al. [34] , which have found no significant cor-
relation between prenatal viral exposure and the occur-
rence of autism [34 –37] . Nevertheless, several studies
have shown significant correlations, primarily with pre-
natal rubella exposure and the development of autism.
Most notable have been several studies by Chess [38, 39]
who has found significant correlations with congenital
rubella and the development of ASD. Other researchers
have observed similar correlations with other viral patho-
gens including, herpes simplex, cytomegalovirus and
varicella zoster [40–42] . Interestingly, Deykin and Mac-
Mahon [35] , in a study which reported no association be-
tween prenatal viral exposure and the development of au-
tism, actually reported an increased frequency of expo-
sure in a ut is ti c s ubjects i n com pa ri so n t o c ont ro l s ubject s.
It is therefore plausible to theorize that an environmental
insult, such as prenatal viral exposure, can act as a trigger
Parker-Athill /Tan
Neurosignals 2010;18:113–128
116
precipitating the aberrant behavioral phenotypes ob-
served in ASD. This is not to say that an environmental
etiology is the only contributor to the development of
ASD. On the contrary, several researchers believe that
these environmental triggers may exacerbate genetic vul-
nerabi litie s in some ind ividuals , or may themselves cause
alterations in gene and/or protein expression, precipitat-
ing the abnormal phenotypes observed in autistic indi-
viduals [11, 43, 44] .
Evidence from Fetal Inflammatory Response
Syndrome
The idea of an ‘environmental insult’ precipitating
neurodevelopmental disorders is not a novel one as sev-
eral compounds, including toxins and heavy metals, have
been shown to cause neurological and congenital abnor-
malities in children exposed prenatally [45–48] . The link
between inflammation and disruption in fetal develop-
ment is also not a novel idea as several researchers have
observed correlations between maternal infections, pre-
term births and neurological disorders in these preterm
infants [11, 4 9–57] . Fetal inflammatory response syn-
drome (FIRS), commonly observed in spontaneous pre-
term labor and considered the fetal counterpart of sys-
temic inflammatory response syndrome, is one example
of how maternal infection can disrupt fetal development.
[54, 58–60] . Researchers, such as Madsen-Bouterse et al.
[58] , have found that intrauterine infection is often a sig-
nif icant contributor to t his syndrome with int ra-a mniot-
ic infection and/or inflammation being present in one
third of the patients with preterm labor. Usually the result
of maternal bacterial infections, FIRS has been strongly
associated with complications in preterm infants, includ-
ing neurological disruption such as cerebral palsy and
systemic FIRS in some instances [61–64] . Similarly, ASD
has also been linked to maternal infection, as epidemio-
logical studies have noted a strong correlation between
maternal infection, particularly with pathogenic agents,
and the occurrence of ASD and other developmental and
psychiatric disorders in resultant offspring [65– 69] . This
research, compounded with clinical findings of immu-
nological disruptions and increased serum cytokine lev-
els in some autistic patients have driven the development
of an ima l mo de ls to in vest iga te th e rol e of ma te rna l i nfec-
tion in the etiology of ASD [70–74] . These studies have
yielded several major findings: (1) maternal infection
triggers an activation of the maternal immune system,
termed MIA; (2) the resulting production of inflamma-
tory cytokines can traverse the blood-placental barrier
and activate the fetal immune system; and (3) this activa-
tion can lead to neurological and immunological distur-
bances that may precipitate the behavioral phenotypes
observed clinically. These studies have also identified
interleukin (IL)-6 as a key cytokine precipitating these
events [12, 75 –78] .
The observations in ASD and models of MIA have
been analogous to those seen in FIRS, as one of the diag-
nostic markers is an increase in IL-6 concentration in t he
umbilical cord plasma and/or the presence of funisitis,
which is an inflammation of the connective tissue of the
umbilical cord, as well as elevations in several other cy-
tokines [12, 54, 58] . The parallels between these two dis-
orders do not end at the neurological and immunological
disruptions mediated by maternal infection and fetal ex-
posure to maternally derived cytokines as several inves-
tigators have also observed genetic alterations, primarily
in genes associated with immune regulation in FIRS in-
fants, a feature also observed in autistic patients [11, 4 3 ,
58] . Altogether, these findings support a probable role of
maternal infection in ASD and further suggest that ma-
ternally derived inf lammatory cytokines can have delete-
rious and persistent effects on the developing fetus not
only precipitating neurological and immunological ab-
normalities, but potentially altering the expression of
genes important in immune regulation and neurodevel-
opment.
Prenatal Viral Exposure, MIA, Genetics and ASD
Genetic dysregulation has long been an area of interest
in the study of ASD as there is a high degree of heritabil-
ity observed in this disorder evidenced by the increased
occurrence in siblings compared to the general popula-
tion, estimated at 3–8% [79– 82] . In comparison to other
genetic disorders, this probability is still low, making the
development of pedigrees difficult; however, a significant
increase in the occurrence of the disorder in identical
twins with a probability estimated at 60–92% has led
many researchers and clinicians to utilize twin studies to
investigate the role of genetics in ASD [80, 83, 84] . Inter-
estingly, although the probability of the occurrence in
fraternal twins is significantly lower than that of identical
twins as expected, it has been shown to be greater than
that observed in other sibling relationships, estimated at
approximately 10%, suggesting a potential role for mater-
nal and environmental inf luences [80, 84, 85] .
In addition to familial inheritance, a strong occur-
rence of ‘autistic-like’ behaviors with genetic disorders,
such as tuberous sclerosis and fragile X syndrome, has
Maternal Immune Activation and Autism
Spectrum Disorder
Neurosignals 2010;18:113–128
117
strengthened the theory of a genetic mode of transmis-
sion. Approximately 18–33% of children with fragile X
syndrome and an estimated 25–50% of children with tu-
berous sclerosis have some degree of ASD, although, like
previously referenced sibling data, these estimates often
vary as a result of differences in diagnostic criteria [2 4,
86–90] . Despite this high degree of comorbidity, only a
small percentage of diagnosed ASD cases are attributable
to these genetic disorders, with 6% of diagnosed autism
cases due to fragile X syndrome and 1–4% to tuberous
sclerosis [87, 90] . Together, these genetic disorders ac-
count for only 10% of diagnosed ASD cases, with the re-
maining 90% still of unknown etiology, although several
other genes have been implicated as polymorphisms and
abnormal expression patterns have been seen in several
autistic individuals [80, 81, 87, 91] . Among those genes
characterized are those involved in the development and
function of the central nervous system (CNS), particu-
larly those regulating neural differentiation, migration,
axonal pathfinding and synapse formation. For example,
the neuroligins, cell adhesion molecules involved in
synaptic maturation and function, have been linked
to autism as mutations and deletions in this gene have
been observed within the autistic population [92]. Simi-
larly, mutations in contactin-associated protein-like 2
(CASPR2), which interacts with neuroligins to promote
synap tic f un ct ion , ha ve a ls o been obse rv ed w it hi n t he a u-
tistic population [92]. Another prominent gene linked to
autism is reelin. Involved in neuronal migration, poly-
morphisms in this gene have been linked to autism, a
finding largely supported by correlations between animal
models of reelin mutations and postmortem analysis of
autistic brains [92]. Additionally, genes involved in im-
mune regulation, including IL-6, and genes important
in several signal transduction pathways have also been
shown to be differentially expressed in autistic individu-
als [93–98] .
MIA: Cytokines and Genetics
Interestingly, researchers have observed neuropatho-
logical and genetic abnormalities similar to those ob-
served in ASD in models of MIA and FIRS patients, sug-
gesting early exposure to inflammatory cytokines may
cause the abnormal expression of some genes (primarily
those involved in immune and CNS regulation) [11, 1 2 ,
43, 58, 72, 99] . In FIRS, for example, genes involved in
MCH antigen presentation, leukocyte adhesion and che-
motaxis are differentially expressed in comparison to
control patients, as are other immune regulatory factors
including cytokines such as IL-6 [58] . In models of MIA,
similar dysregulations have been noted for genes involved
in immune regulation [11, 43, 68] . Utilizing the MIA
model, researchers have also noted dysregulation in genes
involved in the regulation of CNS development and func-
tion, including those involved in neural differentiation
and migration, axonal pathfinding and synapse forma-
tion, maintenance and function, and neurotransmitter
synthesis – genes which are also dysregulated in autistic
individuals [11, 43, 68] .
These observations have mirrored clinical findings in
ASD; however, it is still unclear how these genetic abnor-
malities contribute to etiologic factors. Although de-
scribed as a spectrum disorder, the range of phenotypes
observed clinically do not correlate to the considerable
genetic variations observed. Several researchers now hy-
pothesize that certain genetic polymorphisms, which oc-
cur normally in the population and often have no patho-
logical attributes, can in some individuals, when coupled
with an environmental insult such as maternal infection
and maternal cytokine exposure, lead to the development
of different autistic phenoty pes or ASD [10 0] . This theory
has been used to explain the diverse genetic and pheno-
typic variations seen in autistic individuals, and it has
been suggested that the risk of developing ASD as a result
of maternal infection may be 3- to 7-fold higher in ‘ge-
netically susceptible’ individuals. What this theory does
not explain is the role played by maternal infection, or
more specifically maternally derived inflammatory cyto-
kines in altering the expression of certain genes (primar-
ily those involved in regulation of immune and CNS de-
velopment and function). Although research in FIRS and
MIA models have shown that exposure to maternally de-
rived inflammatory cytokines is sufficient to alter the ex-
pression of several immune related genes, the mechanism
by which this is accomplished is still largely unknown.
IL-6 and Gene Expression
The answer to this question may lie in the innate abil-
it y o f m a ny c ytok in e s t o r eg ul at e g en e e x pr es s io n t h ro ug h
the activation of signal transduction pathways that ulti-
mately activate transcription factors [101] . Cytokines
such as IL-6, for example, activate Janus tyrosine kinase,
mitogen-activated protein and/or other kinases, which in
turn activate transcription factors such as signal trans-
ducer and activator of transcription (STAT) [101, 102] .
These transcription factors in turn regulate the tran-
scription of a range of gene products, binding to the cor-
responding gene promoter regions to induce or repress
gene transcription [102] . During inf lammation for exam-
ple, IL-6-mediated STAT3 activation leads to the in-
Parker-Athill /Tan
Neurosignals 2010;18:113–128
118
creased expression of other cytokines and immune regu-
latory gene s, a nd u lti mately protei ns [103–105] . In neuro-
logical disorders characterized by increased inf lamma-
tion such as Alzheimer’s disease, this increased activity
leads to a persistent inflammatory state with correspond-
ing morphological changes, including increased glial cell
activity [10 6, 107] .
These observations may explain the changes in gene
expression seen in FIRS and ASD patients and animal
models of MIA. In the fetal brain, exposure to maternal-
ly derived inflammatory cytokines may have effects sim-
ilar to what is seen in these neurological disorders, pre-
cipitating the abnormal expression of fetal genes involved
in the development and function of the immune system,
such as what is obser ved in FIRS [78, 106, 108] . Similarly,
cytokines have also been implicated in the regulation of
genes involved in the development and function of the
CNS, analogous to the way they regulate immunological
genes [44, 108] . Cytokines such as IL-6, for example, can
initiate the transcription of neural regulatory genes, im-
portant in the proliferation and differentiation of neural
stem cells (NSC) through the activation of STAT3 and
other transcription factors [44, 109] . In cases where ma-
ternally derived cytokines are present, this can lead to an
increased activation and aberrant expression of these
genes and the neurological and behavioral abnormalities
observed clinically in ASD and models of MIA [11, 12, 50,
68] . It is therefore important not only to examine how
certain genetic polymorphisms can predispose individu-
als to the development of ASD, but also how maternal
cytokine exposure can act as a trigger for this disorder in
susceptible individuals. It is equally important to exam-
ine how this exposure to maternal cytokines can disrupt
the expression of important regulatory genes, and how
these events affect the etiology and phenotypes of ASD,
namely the variations in severity and combinations of
signs and symptoms manifested clinically.
MIA, Neurodevelopment and ASD
Although the genetic component of ASD cannot be
ignored, it has been accepted that maternal infection, or
MIA, may be a significant contributor to the pathology of
developmental disorders (e.g. ASD) and maternal cyto-
kine expression and migration across the placenta, the
main precipitator of the neurological, immunological
and behavioral disruptions observed clinically [51, 54,
110–112] . Furthermore, this exposure to maternal cyto-
kines has been shown to cause behavioral disruptions in
offspring reminiscent of the phenotypes observed clini-
cally in ASD, such as impaired social interaction [12 , 5 0 ,
113] . In examining the potential mechanisms underlying
this phenomenon, it is important to note the physiologi-
cal significance of these molecules during key neurode-
velopmental periods. Under normal physiological condi-
tions, cytokines such as IL-6 are an important part of the
neurodevelopmental signaling cascades involved in sur-
vival, proliferation, differentiation and phenotypic main-
tenance; regulation of neuronal migration and axonal
pathfinding; and synapse formation and elimination [44,
101, 109, 112 , 114–116] . Research has confirmed these
physiological roles showing the regulation of NSC prolif-
eration, survival and differentiation by the gp-130 family,
BMP and members of the interleukin and interferon fam-
ilies [44, 101, 108, 109, 114, 117] .
Cytokines and Neurodevelopment
During normal neurodevelopment, cytokines have
been shown to be present and functional in the fetal
br ain, w it h receptor s id ent if ied on b oth n euronal a nd gli-
al cells [118] . Although present at minimal levels, these
cytokines, such as IL-6 and its receptor, have been de-
tected in the rat cortex as early as embryonic day 18, and
in the human brain as early as 8 weeks [118–121] . Simi-
larly, IL-1 has been detected in the embryonic rat brain,
peaking during embryonic days 18–20 and again at post-
natal day 7 [122] . Although the physiological role of these
cytokines in the developing CNS is not fully understood,
studies have confirmed that they function as important
regulatory molecules and are involved in all phases of
CNS development [44, 121, 123] . Their minimal concen-
trations also suggest that their regulatory activities may
be closely related to circulating concentration, making
the maintenance of homeostasis critical in maintaining
the balance between their physiological and pathological
activities. Several researchers have now begun to exam-
ine the physiological roles of these cytokines in an effort
to better understand their pathological roles in ASD.
Among those examined have been tumor necrosis factor
(TNF), the interferons and interleukins; most notably
IL-6 and other members of the gp-130 family, primarily
due to their observed pleiotropic characteristics. Many of
these cytokines, although originally defined as proin-
flammatory, have now been shown to also possess neuro-
tropic properties regulating cell survival and prolifera-
tion in addition to differentiation and axonal guidance
[44, 114, 117, 122, 124] . IL-6 for example has been shown
to induce the differentiation of NSC into astrocytes and
to a lesser extent neurons and oligodendrocytes while
Maternal Immune Activation and Autism
Spectrum Disorder
Neurosignals 2010;18:113–128
119
promoting the survival of postnatal mesencephalic cate-
choloaminergic neurons and spinal cord cholinergic neu-
rons in culture [125 –128] . TNF- ␣
and IL-1 h ave also bee n
shown to have similar effects, specifically through IL-1
modulating the survival and growth of neuronal and gli-
al cells, and TNF- ␣ inducing synthesis of IL-6 from as-
trocytes and enhancing nerve growth factor release [1 22 ,
129, 130] .
The activities of these cytokines observed in vitro are
believed to mimic their physiological roles, although the
mechanisms by which they exert their effects are still not
fully understood. Contributing to this lack of under-
standing is the observed overlapping function of several
of these cytokines, often able to elicit the same events,
granted through different mechanisms. During CNS
development, for example, cardiotrophin-1 appears to be
the key cytokine inducing glial differentiation, although
other members of the gp-130 family have been shown to
be capable of accomplishing this [44, 114] . These redun-
dant functions may explain why IL-6 has emerged as a
key cytokine in disorders linked to maternal infection
such as FIRS and ASD.
MIA and ASD: Potential Mechanisms
There has been tremendous resea rch showing that sev-
eral cytokines play an integral role in CNS development.
There has also been research suggesting that even minute
changes in the physiological concentrations of these cy-
tokines (e.g. from maternal infections) can be deleterious
to the developing fetus, leading to aberrant gene and pro-
tein expression as well as neurological, immunological
and behavioral abnormalities. It is still unclear, however,
how these effects are mediated as there remains disagree-
ment concerning whether or not these maternal cyto-
kines can traverse the placental barrier to induce re-
sponses in the fetal CNS. Several studies have yielded
conflicting results as some suggest that only negligible
levels of some cytokines pass this barrier, while others
suggest that this does not occur. Whatever the mecha-
nism, it is obvious that MIA somehow triggers activation
of the fetal immune system as studies have shown in-
creases in fetal cytokine expression in the CNS following
exposure to maternal cytokines.
Cytokines and the Placental Barrier
Although there is disagreement as to whether or not
cytokines can traverse the placental barrier, it has been
well accepted that they are ubiquitously expressed in the
placenta, where they serve an important role in the regu-
lation of the maternal-fetal immune interface, aiding in
preventing maternal rejection of the fetus through the
regulation of the maternal immune system [1 31–133] .
During pregnancy, the fetus, which produces alloanti-
gens encoded by paternal genes, can illicit an immune
response from the maternal immune system. Several re-
searchers have hypothesized that instances of spontane-
ous abortions, aberrant fetal growth and recurrent mis-
carriages may be the result of the inability of the placenta
to fully suppress this maternal response to these fetal al-
loantigens, allowing the maternal immune system to at-
tack the developing fetus similar to what is seen in graft-
versus-host rejections and other classical immunological
responses to foreign invaders, such as pathogens [63, 134 –
136] .
Therefore, the placenta functions as an important im-
mu ne ‘org an’, c oord in ating mate rna l-feta l i mmu ne i nte r-
actions in addition to furnishing the metabolic needs of
the developing fetus. Among the resident immunological
molecules in the placenta are maternal immune factors,
including regulatory T cells (T
reg ), human leukocyte an-
tigen-G (HLA-G, a member of the MHC class 1 mole-
cules) and T cell costimulatory molecules in addition to
cytokines and other immune regulatory molecules that
play an important role in regulating the maternal im-
mune system, preventing the rejection of the developing
fetus while still maintaining the capacity to defend the
mother against pathogenic invaders [133, 135, 137] . Un-
der normal conditions, there is an increase in the number
of immu nosuppressive T
reg preceding and after implanta-
tion of the fetus, which prevents the proliferation and ac-
tivation of proinflammatory Th17 cells [13 8 –14 2] . Sev-
eral animal and clinical studies have confirmed this in-
terplay, with observations of T
reg activity, correlated to
increased uterine weight [141, 143, 144] . The role of resi-
dent cytokines becomes increasingly important during
this process as several have been shown to be potent mod-
ulators of T cell regulations capable of shifting the bal-
ance between T
reg and Th17s, recruiting and maintaining
the T
reg population in the placenta [14 5] .
MIA and the Placental Barrier
The role of MIA in disrupting the balance between
regulatory and proinf lammatory T cells remains the fo-
cus of several studies as it is still unknown whether this
event contributes to the phenotypes manifested in autis-
tic patients. What has been shown is the role of cytokines,
particularly IL-6, in maintaining the balance between
T
reg and Th17s. IL-6, an important regulator in the tran-
Parker-Athill /Tan
Neurosignals 2010;18:113–128
120
sition from innate and adaptive immunity, is also a potent
modulator of T cell function, shifting the balance from
T
reg to Th17 cells, downregulating T
reg while promoting
the differentiation of naive T cells into Th17 cells [146 –
148] . This relationship becomes particularly important
when examined in the context of placental function and
MIA. As mentioned previously, T
reg
play an important
role in maintaining tolerance during pregnancy while
suppressing the activity of inflammatory Th17 cells,
wh ich have been impl icated in autoi mmu ne t issue i njury.
Here it can be appreciated that IL-6 expression, the result
of MIA, can promote the expression of Th17 cells while
downregulating T
reg
expression compromising placental
function while promoting a potential autoimmune re-
sponse to the developing fetus [14 4 , 149 –151] . Observa-
tions of an increase in maternal antibodies against neu-
ronal and lymphocytic markers in the serum of mothers
of autistic children further strengthen this hypothesis,
suggesting the involvement of a maternal immune re-
sponse in precipitating this disorder [71, 110] . Addition-
ally, potentially more significant have been observations
of autoimmune disorders in a subset of autistic patients,
ter me d A utoi mmu ne Aut is ti c Disor de r (A A D). T hese pa -
tients exhibit increased proinflammatory cytokines and
other immunological disruptions in Th1/Th2 ratios as
well as auto-antibodies to brain myelin basic protein,
phenomenons researchers have contributed to increases
in Th17 cells potentially precipitated by prenatal viral in-
fection [67, 71, 72, 152, 153] . Equally interesting are ob-
servations made in FIRS, including altered expression of
genes associated with this arm of the immune system,
including MHC antigen presentation, and leukocyte ad-
hesion and chemotaxis [58] . Although more research is
needed to make a direct correlation between these events
and ASD, it is evident that maternal infection may impair
the ability of the placenta to regulate the maternal im-
mune system. It is also evident that resultant impairment
of placental function may allow the passage of maternal
cytokines, and/or elicit the induction of fetal inflamma-
tory cytokines, which in turn disrupts important devel-
opmental pathways, primarily those involved in the de-
velopment and function of CNS and immune system.
Despite these studies, there is still disagreement as to
whether or not these maternal cytokines, produced dur-
ing maternal infection, can traverse the placental barrier
and disrupt normal fetal development. Research in FIRS
has shown that in instances of maternal infection, the
placenta can become inflamed, producing cytokines
such as IL-6 which is a key biological marker in FIRS of-
ten detected in the amniotic fluid and maternal, fetal and
umbilical cord serum [54, 58, 154, 155] . Nevertheless, re-
search focusing on the placental migration of cytokines,
following maternal infection continues to yield contra-
dictory results as some researchers have observed mini-
mal cytokine migration while others note that the levels
that cross the placenta are too negligible to exert any ef-
fect. These contradictory findings may be attributed to
variations in experimental design as comparative studies
have shown that the ability of maternal cytokines to tra-
verse the placental barrier may be highly dependent on
the time of immune challenge. Independent work by sev-
eral groups has shown that IL-6 can traverse the rat pla-
centa to the fetus early in mid-gestation, approximately
on embryonic days 11–13, while during embryonic days
17–19, this is not seen [15 6 , 1 5 7] . This observation may
explain epidemiological findings which suggest 2nd-tri-
mester maternal infection pose the greatest risk for the
development of ASD [158] .
It is worthwhile to note, however, that even with no
observable cytokine migration during late gestation, ma-
ternal infection during this period still results in an in-
crease in cytokine levels in the fetal CNS as there have
been obser vations of increased cytokine mRNA a nd pro-
tein levels, as well as other immunological disruptions in
FIRS infants [54, 59, 78, 154] . Additionally, observations
in models of MIA mimic FIRS findings of increased in-
flammatory cytokines and other immunological events
in the fetal CNS in response to maternal injection, includ-
ing the induction of monocyte chemoattractant protein-1
and increased glial cell reactivity [156, 157] . As LPS does
not traverse the placental barrier, researchers have sug-
gested the presence of intermediary mechanisms, possi-
bly in the maternal-fetal interface, the placenta, that trig-
ger these immunological responses in the fetal CNS.
Whatever the exact mechanism, it is evident that mater-
nal infection and MIA results in increased inf lammation
in the fetal CNS as well as changes in the transcription,
expression and activity of factors that regulate the devel-
opment and function of the CNS and immune system.
IL-6 and STAT3 and ASD
Although several cytokines have been found to be el-
evated in the fetal brain following exposure to maternal
inflammatory cytokines, it has been proposed that IL-6
is the key cytokine responsible for precipitating the path-
ological effects observed in disorders such as FIRS and
ASD. There have been several key pieces of evidence
which have led to the identification of IL-6, including
findings of increased IL-6 levels in the amniotic fluid of
FIRS infants and its aberrant expression and/or function
Maternal Immune Activation and Autism
Spectrum Disorder
Neurosignals 2010;18:113–128
121
in autoimmune disorders, some of which have been as-
sociated w ith ASD, as well as neurological disorders hall-
marked by increased inflammation such as Alzheimer’s
disease [154 , 1 59, 16 0] . Additionally, animal studies in-
volving aberrant expression of IL-6 resulted in neurolog-
ical disorders, with behavioral abnormalities analogous
to clinical observations to disorders such as ASD [10 7,
161, 162] . However, models of MIA which have isolated
IL-6 by selective inhibition of cytokines known to be el-
evated following maternal infection have been more con-
vincing. In one model proposed by Smith et al. [12] , single
maternal injections of several cytokines were coadminis-
tered with their corresponding blocking peptide. Of these
cytokines, only inhibition of IL-6 was sufficient to atten-
uate the behavioral, immunological and neurological ab-
normalities observed in offspring as a result of MIA. This
study showed improvements in measures of social inter-
action, prepulse inhibition and latent inhibition, behav-
ioral measures abnormal in ASD in adult offspring which
were comparable to observations made in control ani-
mals [12] .
The role of IL-6 as a key contributor to these patholo-
gies is further strengthened when its physiological role is
examined. As mentioned previously, IL-6 and other
members of the gp-130 family maintain the proliferation
and survival of NSC through activation of the STAT3
pathway. Additionally, these cytokines regulate neuronal
and axonal pathfinding and the formation and mainte-
nance of functional synapses. In vitro experiments and
comparative in vivo analysis have demonstrated that
many of these cytokines share redundant pathways and
functions, activating analogous pathways to accomplish
the same endpoint. Although an evolutionary favorable
characteristic, it can be seen how pathological expression
of these cytokines can lead to the dysregulation of these
pathways. IL-6 for example has been shown to maintain
the survival of and promote the proliferation of NSC in
vitro, although in vivo experiments have shown that this
may be accomplished by LIF and other members of the
gp-130 family [4 4] . Furthermore, IL-6 has been shown to
promote the differentiation of NSC in vitro, primarily
promoting a glial phenotype although it has been shown
to induce neuronal dif ferentiation in NSC, and mimic the
ac tion of ner ve grow th fa ctor in PC12 cel ls [109, 163, 164] .
In vivo, however, the induction of gliogenesis is attribut -
ed to gp-130 family member, cardiotrophin-1 although
studies have confirmed the presence of IL-6 receptors
and IL-6 during early embryonic time points [44, 108] . It
i
s plausible to hypothesize that during maternal infec-
tion, maternally derived IL-6 can traverse the placenta to
act on the fetal brain, inducing the synthesis of fetal IL-6
and/or activating common pathways such as the STAT3
pathway as several studies have shown negligible migra-
tion of IL-6 preferentially to other cytokines [165, 16 6] .
Once elevated, IL-6 can induce actions similar to those
seen in vitro, such as increased cell survival and prolif-
eration. Although in isolation or in conditions of neuro-
logical injury, these events may seem innocuous or even
beneficial; during development, these events may lead to
abnormal increases in neuronal and/or glial populations,
as the negligible expression of cytokines, such as IL-6 in
the fetal CNS, suggest that these processes are closely reg-
ulated by circulating concentrations of these cytokines.
This situation can be put into perspective when we exam-
ine clinical observations of ASD, such as increased neu-
ronal numbers in certain areas of the brain, which is be-
lieved to be a contributor to the behavioral abnormalities
manifested in these patients.
T he rol e of IL -6 in ind ucing di ff ere ntia ti on, or r eg ul at-
ing axonal guidance and synapse formation, can also be
examined in the context of clinical observations. During
normal CNS development, induction of differentiation is
highly controlled, with neurogenesis preceding gliogen-
esis. These events are not only controlled by cytokine-
induced activation of necessary pathways, but also by in-
hibition of transcription factors and methylation of gene
loci [4 4] . Duri ng neurogenesis for example, STAT3, which
has been shown to be a key transcription factor in the ac-
tivation of gliogenic genes is inhibited, by protein modi-
fication in addition to other mechanisms. Similarly, glio-
genic genes are methylated, preventing the binding of
STAT3 and these genes [44] . As neurogenesis proceeds,
proteins ass ociated wit h embryonic neurons, such a s car-
diotrophin-1 accumulates, activating the STAT3 pathway
[16 7] . This event coincides with the demethylation of
gliogenic genes as well as the inhibition of neurogenic
transcription factors. With pathological IL-6 expression,
such as that derived from maternal sources, premature
differentiation can mean disruption in neuronal or glial
populations. These events can also lead to disruption of
other important processes such as neuronal migration,
axonal pathfinding and synapse formation. Several re-
searchers hypothesize that these neurological events pre-
cipitate resultant behavioral abnormalities observed clin-
ically in autistic patients. These findings not only impli-
cate a potential ‘trigger’ for the development of ASD, but
also identify potential biological markers which may be
utilized to diagnose this disorder at earlier time points
similarly to clinical diagnosis of FIRS. Early diagnosis
does not necessarily mean early intervention, but the
Parker-Athill /Tan
Neurosignals 2010;18:113–128
122
identification of a biological marker may enable the use
of pharmacological intervention in the management of
this disorder.
Viral Pathogens, MIA and ASD
To date several researchers have cited a viral-induced
activation of the maternal immune system, MIA, as the
primary contributor to the behavioral abnormalities ob-
served in animal models of MIA and in ASD [68] . Smith
et al. [1 2 ] , utiliz ing an anima l model of MIA have strength-
ened this hypothesis, finding that the activation of the
maternal im mune system in response to viral e xposu re is
a key mechanism in precipitating the behavioral abnor-
ma lities in M IA offspr ing. Furthermore, t his group iden-
tified IL-6 as a key cytokine in this mechanism as inhib-
iting this cytokine attenuated the behavioral abnormali-
ties observed in offspring exposed to MIA prenatally [1 2] .
Other groups, however, have cited a potential alternative
mechanism to the changes seen in these offspring, citing
the actions of the viral pathogen itself as a key precipita-
tor in ASD neuropathologies. In a study in which preg-
nant mice were injected with human influenza at embry-
onic day 9, Fatemi et al. [11] observed changes in protein
expression in several key proteins involved in neurode-
velopment, most notable of which was connexin 43. In
another study by the same group, alternations in expres-
sion of several genes including those regulating myelin
expression were also observed following prenatal viral
infection [43, 168, 169] .
It is important to note that although Smith et al. [1 2]
and others cited increases in maternal cytokine levels,
most notably IL-6, as a key factor in these disruptions,
they also noted changes in gene expression following vi-
ral exposure. Additionally, in cases of FIRS, although im-
munological disruptions such as increased IL-6 levels
were noted as one of the most significant characteristics,
changes in gene expression were also observed in genes
involved in immune regulation [58] . Fatemi’s work does
not preclude the role of the maternal immune response in
precipitating the changes observed in models of MIA and
clinically in ASD, but rather suggest the importance of
examining the mechanistic aspects of viral activation of
the immune system and the potential downstream ef fects
on gene transcription and protein expression. It can be
argued that either mechanism may be a precipitating fac-
tor as it is the initial viral exposure that initiates the acti-
vation of the maternal immune system and resultant in-
flammatory cascade. Although it is unclear whether the
changes we observed in MIA and clinically in ASD can
be attributed solely to either mechanism, or even wheth-
er these two can be separated, it is evident that prenatal
viral exposure leads to an increase in maternal cytokine
exposure and IL-6 levels and altered gene expression, and
that these factors have the potential to precipitate the
behavioral and neuropathologies observed clinically in
ASD.
Current Therapeutic Approaches
Currently there is no cure for ASD and therapeutic in-
tervention focuses primarily on the management of
symptoms, utilizing behavioral therapy to control the ab-
norma l behavioral phenotypes associated with the disor-
der. Although pharmacological intervention is not com-
mo nl y u se d i n t he ma na geme nt of A SD, it is of te n ut il iz ed
in the treatment of comorbid disorders, which frequently
occur with ASD, including seizures, increased aggression
and other pharmaceutically responsive conditions. The
use of palliative care in the management of development
disorders is not uncommon, as many, especially those of
genetic origin are incurable, making the management of
symptoms the only possible therapeutic intervention.
Recent research in ASD has highlighted the role of ma-
ternal infection in the etiology of ASD. More specifically,
they have identified exposure to maternal cytokines, pri-
marily IL-6, as a key environmental ‘trigger’ precipitating
the development of ASD in some individuals. These find-
ings are significant not only in understanding the etiology
of ASD, but the identification of IL-6 may provide a po-
tential biological marker enabling the early diagnosis of
the disorder and earlier therapeutic intervention. The
identification of IL-6 has also provided a potential thera-
peu ti c t ar ge t a s model s o f M IA ha ve s ho wn th at in hi biti ng
IL-6 during maternal infection can attenuate the behav-
ioral abnormalities observed in MIA offspring. In studies
by Smith et al. [12] , coad ministration of poly(I:C), used to
induce MIA and IL-6 neutralizing antibody, attenuated
the behavioral abnormalities observed in the offspring, as
the y obs er ved imp roveme nt i n prepu ls e inhibit ion a nd la-
tent inhibition comparable to observations in control an-
imals. Similarly, research by our group has also conf irmed
IL-6 as a potential therapeutic target, sufficient to attenu-
ate the symptoms associated with ASD. Furthermore, we
discovered that inhibition of IL-6-induced activation of
STAT3 was also able to attenuate the behavioral and im-
munological abnormalities observed in MIA offspring. In
vitro experiments utilizing an LPS-microglial model to
induce inf lammation showed that biof lavonoid pretreat-
ment or cotreatment was sufficient to inhibit the produc-
Maternal Immune Activation and Autism
Spectrum Disorder
Neurosignals 2010;18:113–128
123
tion of IL-6 and TNF- ␣ , while IL-6 and bioflavonoid co-
treatment of neuronal cultures showed t hat biof lavonoids
could also inhibit IL-6-induced activation of STAT3 [113] .
These results, which support previous findings by our
group and others, suggest that bioflavonoid treatment not
only has the potential to inhibit pathological cytokine
production, but also to inhibit cytokine-induced activa-
tion of key signaling molecules such as STAT3 [17 0 , 171] .
Furthermore, in vivo experiments have shown similar re-
sults, with prophylactic bioflavonoid treatment reducing
cytokine expression and STAT3 activity in MIA offspring
[113] . These observations suggest that it is not only pos-
sible to attenuate the pathological increase in cytokine ex-
pression resulting from maternal infection, but therapeu-
tic intervention to attenuate the resultant activation of
critical signaling pathways may also be possible. These
observations further suggest that prophylactic interven-
tion may serve a protective role, especially in instances of
known maternal infection. Similarly to how folic acid has
been shown to be essential in the prevention of cephalic
disorders, inhibition of pathological maternal cytokine
expression may have therapeutic potential. Furthermore,
postnatal bioflavonoid treatment to attenuate the activi-
ties of IL-6, such as pathological activation of STAT3
pathways, may prove to be of potential therapeutic value
by providing more than a palliative treatment for ASD.
Although these results are preliminary, and there are still
many unanswered questions concerning the role mater-
nal infection plays in precipitating ASD, it is evident that
the IL-6 plays a key role in precipitating this disorder,
making it a key target for therapeutic intervention. It is
necessary not only to determine the mechanism by which
maternal infection and IL-6 precipitate this disorder and
how therapeutic intervention can aid in managing the
symptoms associated with ASD, but also to attenuate the
symptoms of this disorder.
Discussion
Since its first use in the early 1900s to describe a clus-
ter of abnormal symptoms observed in a group of schizo-
phrenics, and later similar symptoms in children, there
have been significant advances in the understanding and
treatment of ASD. There are still, however, many unan-
swered questions concerning the etiology of ASD as ge-
netic variability among autistic individuals coupled with
diverse phenotypic presentations have complicated the
identification of a single causative agent. Nevertheless,
researchers have made significant progress and have
identified several genes differentially expressed in autis-
tic individuals. Although these genes are not sufficient to
cause ASD, they may provide a way to identify geneti-
cally susceptible individuals, or aid in the diagnosis of
this disorder. Recently, maternal infection and fetal ex-
posure to maternal cytokines, primarily IL-6, have been
identified as potential environmental ‘trigger’, which,
when coupled with certain genetic polymorphism, may
lead to the development of ASD. Although the exact
mechanism by which IL-6 elicits these events is un-
known, its identification provides a potential diagnostic
marker and therapeutic intervention point for ASD.
These advancements are promising; however, several
unanswered questions still remain, prompting the need
for more research. The identification of IL-6 as a potential
trigger, for example, has raised questions concerning the
ability of cytokines to traverse the placental barrier, and
whether or not this passage is confined to certain devel-
opmental time points. Also unknown is whether or not
the placenta itself contributes to the increase in fetal cy-
tokine expression, as this has been observed in the ab-
sence of maternal cytokine migration. Researchers are
also faced with the question concerning the mechanism
by which IL-6 induces the abnormalities observed clini-
cally in autism and whether or not inhibition of patho-
logical IL-6 is sufficient to attenuate these abnormalities.
It is also unclear as to whether or not maternally derived
IL-6 is sufficient to promote the development of ASD or
whether certain genetic polymorphisms are needed. Al-
though animal models of MIA suggest that IL-6 is suffi-
cient to induce the behavioral, immunological and neu-
rological abnormalities observed in ASD, it is still unclear
whether these findings completely mirror clinical obser-
vations. The role of genetics in the etiology of ASD also
poses several questions including why some people, ex-
posed prenatally to maternal cytokines may develop ASD
while others do not.
As we investigate the etiology of this disorder, there
are also important questions that arise concerning the
diagnosis of this disorder. Although it is well accepted
that autism is a part of a spectrum of disorders collec-
tively referred to as ASD, there are some within the re-
search and clinical community that would classify it as a
syndrome, a singular manifestation of different disor-
ders. This approach may explain the difficulty in deter-
mining the exact etiology of the disorder as well as the
diversity of phenotypes presented clinically. Proponents
of the syndrome approach argue that the term spectrum
sug gests a si ng ul ar di sor de r w it h c li n ica l s ym pt om s v ar y-
ing within a given phenotypic range or spectrum. As a
Parker-Athill /Tan
Neurosignals 2010;18:113–128
124
syndrome, researchers such as Mary Coleman and Chris-
topher Gillberg suggest that autism is a singular pheno-
typic presentation of different diseases with varying eti-
ologies [17 2] . This approach suggests that autism may be
a phenotype manifested as a result of different diseases
and etiologies acting singularly or synergistically to pro-
duce the behavioral symptoms manifested clinically. Al-
though Coleman’s and Gillberg’s suggestions differ from
current norms within the ASD community, they do ac-
knowledge the diagnostic importance of investigating
autism as a spect rum disorder as it is necessa ry in t he i ni-
tial diagnosis. It is for the investigation of etiologies and
the provision of therapeutics that these authors propose
newer approaches, as the treatment of autism as a product
of its etiology may be advantageous in providing more
patient-tailored treatments. Whether a syndrome or a
spectrum, it is evident that autism or ASD is the result of
several etiologies. It is also evident that environmental
triggers, when coupled with genetic polymorphisms, may
lead to diverse phenotypic presentations. What is not
known is how these factors, genetics and environment,
interact in a given individual to precipitate this disorder.
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made, these advancements have also created more ques-
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other discoveries, has paved the way for improved diag-
nostic criteria in addition to new therapeutic intervention
points. The potential for IL-6 as an intervention point is
also promising as it provides a measurable diagnostic
marker in addition to potential therapeutic target. With
these advancements, early therapeutic intervention, with
the goal of significantly attenuating or alleviating the
symptoms of ASD, may eventually become a treatment
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Acknowledgments
This work was supported by the Silver Endowment and the
NIH/NIMH (R21MH087849, J.T.). J.T. holds the Silver Chair in
Developmental Neurobiology. We thank Demian Obregon (Uni-
versity of South Florida) for his helpful advice.
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