Maternal immune activation: implications for neuropsychiatric
disorders
Myka L. Estes and A. Kimberley McAllister
*
Abstract
Epidemiological evidence implicates maternal infection as a risk factor for autism spectrum
disorder and schizophrenia. Animal models corroborate this link and demonstrate that maternal
immune activation (MIA) alone is sufficient to impart lifelong neuropathology and altered
behaviors in offspring. This review describes common principles revealed by these models,
highlighting recent findings that strengthen their relevance for schizophrenia and autism and are
starting to reveal the molecular mechanisms underlying the effects of MIA on offspring. The role
of MIA as a primer for a much wider range of psychiatric and neurologic disorders is also
discussed. Finally, the need for more research in this nascent field and the implications for
identifying, and developing new treatments for, individuals at heightened risk for neuro-immune
disorders are considered.
The Zika virus and its accompanying risk of microcephaly(1) has finally turned public
attention to the detrimental effects of maternal infection. While images of microcephalic
newborns evoke outcry and require government action, the direct effects of Zika are only
one part of a much larger global health hazard. An acute maternal immune response initiated
by many common viruses is sufficient to cause lifelong changes in brain function and
behavior of offspring in animal models(2). While Zika and other pathogens may confer
higher risk of specific disorders, growing evidence suggests that maternal immune activation
(MIA) in the absence of a pathogen may increase the risk of a broad spectrum of central
nervous system (CNS) disorders in humans(3)(Figure 1).
Maternal infection and psychiatric disorders
The association between maternal infection and neurodevelopmental disorders is
longstanding, but not without controversy. Following the 1964 rubella pandemic, the
incidence of two neurodevelopmental disorders, autism (ASD) and schizophrenia (SZ), rose
from less than 1% in the unexposed population to about 13% and 20% respectively(2).
Subsequent studies charting historic outbreaks of flu, measles, mumps, chickenpox, and
polio, revealed an association with ASD, SZ, and several mood disorders(4). However, not
all ecological studies have replicated these associations(5). The differing conclusions may
stem from differences in estimating the exposed population(5). Nevertheless, several
prospective studies following birth cohorts(3, 6) are consistent with an association between
*
Corresponding Author: A. Kimberley McAllister, Ph.D., Center for Neuroscience, UC Davis, One Shields Avenue, Davis, CA 95618,
Phone: (530) 752-8114, kmcallister@ucdavis.edu.
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Published in final edited form as:
Science
. 2016 August 19; 353(6301): 772–777. doi:10.1126/science.aag3194.
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viral infection and psychiatric disorders in offspring and add other classes of pathogens to
the list: namely, bacterial infections including pneumonia, sinusitis, and tonsillitis, and the
parasite
Toxoplasma gondii
(2, 3).
How can such a diverse group of pathogens confer similar risk of neurodevelopmental
disorders? Common to the implicated pathogens is the maternal immune response. In
support of this, enduring fevers above a certain threshold pose the greatest risk(6). It follows
that immune system activation above that threshold due to any environmental insult or
genetic predisposition would also increase risk. Indeed, maternal autoimmune disorders,
allergies, asthma, acute stress, and exposure to environmental pollutants—all of which lead
to elevated immune responses—have been linked to an enhanced risk of ASD and SZ(3, 6).
These findings may help to contextualize two recent prospective studies that failed to find a
significant association between prenatal infection and SZ after adjusting for parental
infection in general, parental psychiatric disorder, and socioeconomic status(7, 8). For
example, in one study, the modest association between prenatal infection and SZ was not
significantly different from an association with a generalized familial liability to develop
severe infection(8). This finding may again point to the importance of the maternal immune
background. A paternal association implicates the immunogenetic background of the fetus.
Thus, the immune status of both mother and child determines the vulnerability to MIA. A
second study found a synergism between maternal infection and maternal psychiatric
disorders(7). Since many individuals with SZ have immune abnormalities, this association
could point to maternal immune status as well as synergism with genetic risk factors. If MIA
is a primer for a wide-array of disorders then further work is necessary to identify
additive(9) and synergizing risk factors(7), which may be hidden in the adjusted models
typically used in these studies.
Explosive growth in the human population, urbanization, and climate change combine to
drive emerging infectious diseases like Zika(10). Simultaneously, pervasive poverty that
limits access to childhood vaccinations, together with baseless fear of vaccinations within
affluent groups, has led to a resurgence in infectious diseases of the past, like measles,
mumps, rubella, whooping cough, and even polio(11). Increased exposure to new and old
viruses heightens the risk of pregnant women contracting one of these diseases and thereby
may increase the likelihood that her children will develop CNS disorders. Together, the
increased presence of communicable diseases combined with an uptick in autoimmune
disorders(6) could account for a significant proportion of the concerning recent increase in
incidence of neurodevelopmental disorders(12).
Animal models of maternal infection
Evidence for these associations has been growing steadily more compelling, but
epidemiology alone cannot establish a causal relationship between maternal immune
activation (MIA) and risk of neurodevelopmental disorders. Thus, this association in humans
will likely remain controversial at least into the near future. Humans are genetically,
ecologically, and behaviorally heterogeneous, all of which can influence susceptibility to
disease and therefore complicate and undermine detection of causal relationships. Clinical
research is also limited in its ability to identify the molecular pathways downstream of
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maternal infection since humans cannot be subject to invasive experimentation. Moreover,
there is currently not an effective way to identify the at-risk pregnancies. The majority of
pregnancies even at high risk will lead to healthy offspring and the resulting CNS disorders
in offspring often do not appear for many years after birth and appear to be influenced by
postnatal risk factors that synergize with genetic and prenatal risk to act as “second hits”(3,
13–15). Clearly, there is a compelling need for long-term and large prospective studies to
identify the specific aspects of infection during pregnancy (the type of pathogen, extent of
fever, timing of infection, etc.), as well as synergies with postnatal exposures, that lead to
heightened risk of CNS disorders in offspring.
Because of these challenges of studying MIA in humans, animal research is therefore
essential for identifying causal mechanisms and developing new diagnostic tools and
therapeutics. Indeed, a causal relationship between maternal infection and ASD and SZ-
related behavioral abnormalities has been clearly demonstrated using rodent and, more
recently, non-human primate (NHP), animal models. In these models, pregnant animals are
exposed to an immunological manipulation at a specific gestational stage. The behavior and
brain structure and function of MIA offspring are then compared to those of control
offspring. The most common immunogens used in these studies include influenza infection
and exposure to viral (polyinosinic:polycytidylic (poly(I:C)) and bacterial
(lipopolysaccharide (LPS)) mimics that cause MIA(14). These MIA animal models meet all
of the criteria required for validity for a disease model: they mimic a known disease-related
risk factor (construct validity), they exhibit a remarkably wide range of disease-related
symptoms (face validity), and they can be used to predict the efficacy of treatments
(predictive validity). Each specific MIA model has important advantages and disadvantages.
Differences in gestational age, immunogen, dose, and timing lead to overlapping and distinct
phenotypic signatures that are critical factors in evaluating their use as preclinical models.
The common principles revealed by these models are included in this overview of the field.
Please see other recent reviews for details on each model(4, 14) as well as additional
maternal immune(14), maternal antibody(16), autoimmune(17), and stress models(18).
Rodent MIA models
The rodent MIA models manifest a remarkably comprehensive range of SZ and ASD-related
behavioral abnormalities. Offspring from the poly(I:C) rodent model, in particular, exhibit
most of the core behavioral symptoms of ASD—abnormal communication, abnormal social
behaviors, and increased repetitive behaviors(2–4, 6, 14). Offspring from these MIA models
also show many additional SZ- and ASD-related behaviors, including decreased
sensorimotor gating (which measures the ability of the brain to filter out extraneous
information), deficits in working memory and cognitive flexibility, increased anxiety, and
enhanced sensitivity to amphetamines(2, 3, 14). Importantly, many of these behaviors can be
alleviated by antipsychotic drugs, supporting the disease-relevance of these models(3, 4, 14).
In addition to these aberrant behaviors, adult MIA offspring also exhibit neuropathologies
emerging at specific developmental ages, especially SZ-associated reduced cortical thickness
and hippocampal (HC) volume and increased ventricular size as well as ASD-associated
aberrations in Purkinje cells(2–4, 14). Several studies have also recently reported deficits in
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dendritic spine density, levels of synaptic proteins, synaptic transmission, long-term
plasticity, and cortical malformations(4, 19–24). However, most of these measures have been
studied in single brain regions from single models at a single age. So, while it is likely that
MIA causes changes in synaptic connectivity, function, and plasticity, elucidating the details
and common principles remains an important goal for the future.
Recent work has also uncovered neurochemical changes in adult MIA offspring that are
characteristic of SZ and ASD(3, 4, 14, 25) (Figure 2). Serotonin and dopaminergic signaling
is altered in MIA offspring across models(3, 4, 14). Additionally, specific changes in
inhibitory neurotransmission have been linked to both SZ and ASD(26) and similar
reductions in several components of the GABA system are present in the brains of MIA
offspring(3, 4, 14, 25, 27–29). One of the most exciting recent advances in the MIA field is
the discovery of deficits in the function of parvalbumin (PV) cells, known to be selectively
altered in SZ, in the brains of adult MIA offspring(3, 14, 22, 30). MIA causes a specific
reduction in inhibition from PV cells onto pyramidal neurons that is sufficient to cause
deficits in attentional set shifting and enhance anxiety-related behavior in offspring(30),
similar to behavioral changes in SZ patients with confirmed evidence of gestational
infection(31). Consistent with predictions from a loss of perisomatic inhibition of pyramidal
cells in the prefrontal cortex (PFC)(4), MIA offspring exhibit increased power in the theta
band(32) and reduced EEG coherence specifically between the HC and mPFC(4). These
findings mirror reductions in long-range signaling in SZ(33).
NHP MIA models
Even though these rodent models have remarkably strong face, construct, and predictive
validity for SZ and ASD, the potential of using rodents to tell us about psychiatric disorders
that are so inherently human has remained controversial. To bridge the gap between rodents
and humans, several groups have established rhesus macaque MIA models. Some of these
NHP models display behavioral symptoms of ASD and SZ—increased repetitive behaviors,
abnormal communication and impaired social interactions—that start at weaning and
increase in intensity with age(4, 14, 34). MIA also alters gray and white matter volume in an
immunogen-specific manner(4) and causes subtle changes in dendritic arborization(35) in
neonatal NHP offspring. An outstanding question that can be addressed uniquely by NHP
models is whether molecular signatures of MIA identified in rodent models underlie
phenotypes similar to ASD and SZ in humans. Answering this question in the future will be
a major advantage for generating new therapies.
Considerations in interpreting MIA models
MIA models utilize a surprisingly wide range of protocols that vary in the type, as well as
the timing, mode of delivery, and dose of immunogen used. The type of immunogen dictates
the nature of the immune response and downstream phenotypes. The timing of exposure is
also key in determining the nature and severity of the outcomes (Figure 3)(14). MIA in early
versus late gestation causes distinct fetal brain cytokine responses and changes in
neuropathology and behavior in adult offspring(14, 36), but whether the timing of exposure
leads to distinct CNS disorders remains unknown. MIA outcomes can also be dependent on
the mouse strain(37, 38), individual differences in maternal immune responsiveness within a
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strain(39), and gender differences in offspring(4, 14). Finally, the mode of delivery and dose
of the immunogen also dictate the outcome in offspring following MIA, implying that there
must be a threshold of MIA required to produce ASD and SZ-like phenotypes in
offspring(14, 30). A key advance would be quantifying the threshold for MIA to induce
disease-relevant phenotypes. This would allow better comparison between studies and more
effective use of the model in the preclinical arena(29).
MIA as a disease primer
In humans, most maternal infections do not lead to SZ or ASD in offspring(40); thus, it is
currently thought that multiple “hits” (exposure to more than one risk factor) may be
required for disease induction (Figure 1). MIA appears to act as a “disease primer”(14) to
make an individual more susceptible to the effects of genetic mutations and environmental
exposures in triggering disease-related symptoms later in life(41). Consistent with this idea,
the incidence of both ASD and SZ is much higher in families with autoimmune disorders(2,
6) and the effect of maternal infection in increasing SZ risk is greater in families with a
history of SZ(3). Indeed, low dose poly(I:C) MIA synergizes with mutations in SZ and
ASD-associated genes, including
DISC1
,
NRG1
(encodes Neuregulin-1),
NR4A2
(encodes
Nurr1), and
TSC2
to cause greater effects than either insult alone(3, 4, 14).
While studies of interactions between MIA and environmental risk factors have only
recently begun, the results thus far using animal models suggest that even subclinical
maternal infection can make offspring much more vulnerable to second “hits” (Figure 1).
Sub-threshold MIA increases the likelihood of environmental risk factors, such as stress and
drug use, to cause SZ and ASD-related phenotypes in offspring(3, 14). Peripubertal stress
causes synergistic effects in subclinical poly(I:C) MIA offspring on a wide range of SZ and
ASD-related behaviors and molecular phenotypes(3, 4, 14). Similarly, adolescent cannabis
exposure causes synergistic effects in subclinical MIA mice(4, 42). Combined insults can
even change the nature of the phenotype. LPS MIA alone results in NMDAR hypofunction
and a loss of HC long-term plasticity in adolescent rats but, when combined with restraint
stress, the outcome switches to the opposite phenotypes(4). While the molecular mechanism
of MIA as a disease primer is unknown, brain region-specific alterations in epigenetic marks
at several loci including
DISC1
could be a molecular signature of its priming effect(43, 44).
There is also growing evidence that MIA is associated with a much wider array of
psychiatric and neurologic disorders than just ASD and SZ. Recently, MIA has been linked
to anxiety, major depressive disorder (MDD), and bipolar disorder (BPD) in people (3, 45–
47). These seemingly distinct disorders share a surprising number of genetic and
environmental risk factors, behavioral abnormalities, and alterations in brain structure and
function(3, 48, 49). MIA animal models also exhibit behavioral and neurochemical
alterations consistent with depression and anxiety(3, 47, 50). MIA has even been shown
recently to prime mice for degenerative diseases during aging, including Alzheimer’s
disease(51).
These links of MIA to an increasing array of diseases as diverse as neurodevelopmental
disorders (ASD) and neurodegenerative disease (Alzheimer’s disease) that afflict individuals
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