Prenatal and Postnatal Animal Models of
Immune Activation: Relevance to a Range
of Neurodevelopmental Disorders
Louise Harvey, Patricia Boksa
Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Verdun,
Quebec, Canada H4H 1R3
Received 15 June 2012; accepted 18 June 2012
lished links between immune activation during the pre-
natal or early postnatal period and increased risk of
developing a range of neurodevelopment disorders in
later life. Animal models have been used to great effect
to explore the ramifications of immune activation during
gestation and neonatal life. A range of behavioral, neu-
rochemical, molecular, and structural outcome meas-
ures associated with schizophrenia, autism, cerebral
palsy, and epilepsy have been assessed in models of pre-
natal and postnatal immune activation. However, the
epidemiology-driven disease-first approach taken by
some studies can be limiting and, despite the wealth of
data, there is a lack of consensus in the literature as to
the specific dose, timing, and nature of the immunogen
that results in replicable and reproducible changes
related to a single disease phenotype. In this review, we
Epidemiological evidence has estab-
highlight a number of similarities and differences in
models of prenatal and postnatal immune activation
currently being used to investigate the origins of schizo-
phrenia, autism, cerebral palsy, epilepsy, and Parkin-
son’s disease. However, we describe a lack of synthesis
not only between but also within disease-specific models.
Our inability to compare the equivalency dose of immu-
nogen used is identified as a significant yet easily rem-
edied problem. We ask whether early life exposure to
infection should be described as a disease-specific or
general vulnerability factor for neurodevelopmental dis-
orders and discuss the implications that either classifica-
tion has on the design, strengths and limitations
of future experiments.
' 2012 Wiley Periodicals, Inc. Develop
Neurobiol 72: 1335–1348, 2012
activation; neurodevelopment; disease
Early life events can have significant effects on an
organism’s long-term health and wellbeing during
adulthood. Since the \Barker hypothesis" drew atten-
tion to the impact of prenatal nutrition on the risk of
subsequent adult-onset disorders such as diabetes, cardi-
ovascular disease, and hypertension (Barker and Mar-
tyn, 1992), this field, also known as the developmental
origins of health and disease, has expanded to demon-
strate how influential the prenatal environment is on a
wide range of adult health outcomes (Barker, 2004;
Sinclair et al., 2007; Sinclair and Singh, 2007). With
respect to the central nervous system (CNS), early
events that have been implicated in altering the trajec-
tory of neurodevelopment include pregnancy and birth
complications, maternal/neonatal exposures to nutri-
tional deficiency, stress, drugs or toxins, and postnatal
social deprivation (Schlotz and Phillips, 2009). Infec-
tion with resulting immune activation is another such
insult, and the focus of the current article is on how
animal models of prenatal and postnatal immune activa-
tion are being used to study the role of early life infec-
tion in the etiology of neurodevelopmental disorders.
Prenatal or early postnatal immune activation has
been implicated in a number of major neurodevelop-
mental disorders, including schizophrenia, autism, cere-
Correspondence to: P. Boksa (firstname.lastname@example.org).
' 2012 Wiley Periodicals, Inc.
Published online 25 June 2012 in Wiley Online Library
bral palsy, and epilepsy (Pakula et al., 2009; Brown
and Derkits, 2010; Landrigan, 2010). While disorders
like schizophrenia and autism appear to be uniquely
human, certain structural, molecular, and behavioral
abnormalities found in these human disorders can be
assessed in animals species commonly used for preclin-
ical research. It will be recalled that the etiologies of
disorders like schizophrenia, autism, or cerebral palsy
are multifactorial, likely involving a complex interplay
between genetic and environmental factors. Thus, it
should not be surprising if CNS effects produced by a
single risk factor in isolation, like prenatal infection,
are rather subtle, and may not mimic the entire spec-
trum of abnormalities characteristic of the disorder.
Nonetheless, the development of animal models allows
us to address specific questions about effects of expo-
sure to early life infection, e.g., the timing of the criti-
cal period of exposure to the immune activation; the
duration and severity of the inflammatory response; the
trajectory of neurodevelopmental changes during
juvenile and adult life; the mechanisms mediating
effects of immune activation on neurodevelopment;
and responses to potential therapeutic intervention.
The approach taken by many researchers in this
area is to focus on a specific disorder and to work with
a particular model of prenatal or postnatal immune
activation, which attempts to mimic the epidemiology
of the disorder, concentrating on assessing end points
characteristic of that disorder as outcome measures.
The aim of this review is to provide a brief overview
of the range of models of early life immune activation
currently being used within the context of various neu-
rodevelopmental diseases. After a brief introduction to
the immunogens commonly used to induce immune
activation, we will describe some of the models,
mainly in rodents, that are commonly used to examine
effects of prenatal or postnatal immune activation in
relation to schizophrenia, autism, cerebral palsy, epi-
lepsy, and other disorders. Rather than aiming to be
exhaustive, we will use a selection of examples to
compare and contrast abnormalities in disease-specific
endpoints observed in these models.
It is possible that a better integration of findings
across specific disease-based models might enhance
our understanding of the overall effects of early life
exposure to infection on neurodevelopment. There-
fore, in the course of the review, we hope to highlight
some of the similarities and differences between these
models and suggest that a broadening of the outcome
measures assessed in some already well-established
models or collaboration between researchers with
interests in different diseases might be a valuable
option to consider.
IMMUNOGENS USED TO MODEL
PRENATAL OR POSTNATAL IMMUNE
The most common immunogens used to induce
inflammation in pregnant mice and rats are lipopoly-
saccharide (LPS) and polyinosinic:polycytidylic acid
[poly(I:C)]. LPS, a component of the cell wall of
Gram negative bacteria, is a molecular immunogen
used to mimic a bacterial infection whereas poly(I:C),
a synthetic, double-stranded RNA, mimics a viral
infection. Both immunogens bind to toll-like recep-
tors [LPS to TLR-4, poly(I:C) to TLR-3], initiating a
signaling cascade that leads to activation of transcrip-
tion factors, such as nuclear factor kappa B (NFjB)
and subsequent transcription of genes coding for pro-
and anti-inflammatory mediators such as cytokines
[interleukin (IL)-1, tumor necrosis factor (TNF)-a,
IL-6, and interferons (IFNs)], chemokines, and com-
plement proteins. IL-6 then acts in the brain to induce
cyclooxygenase-2-mediated synthesis of prostaglan-
dins in the hypothalamus, which can mediate a fever
response (Roth et al., 2009). Although there are broad
similarities in some components of the proinflamma-
tory cytokine cascade induced by both LPS and
poly(I:C), there can be significant differences in the
magnitude of cytokine responses induced by these
two types of immunogens, as well as both quantita-
tive and qualitative differences in the cell types that
respond to activation, the profile of cytokine induc-
tion, and activation of downstream signaling cascades
(e.g., Bsibsi et al., 2006; Reimer et al., 2008; Figueir-
edo et al., 2009). Also, importantly for models of
inflammation during pregnancy, TLR3 and TLR4
may be differentially modulated by hormones, includ-
ing progesterone (Jones et al., 2010), whose levels
increase throughout pregnancy, peaking during late
pregnancy in humans and rats and falling just before
parturition in the rat (Bridges, 1984).
When comparing findings within models of early
life immune activation, one simple but important fac-
tor to consider is the dosage of immunogen used.
These models make widespread use of LPS as the
immune activator; however, despite its frequency of
use, it is difficult to compare LPS dosages across stud-
ies as it is known that the bioactivity of LPS per milli-
gram is dependent on the lot and serotype of the strain
of Escherichia coli (Ray et al., 1991; Akarsu and
Mamuk, 2007). This results in an inability to effec-
tively compare and contrast between models, particu-
larly in instances where authors do not provide details
of in vivo or in vitro bioactivity assays. Similar to the
1336 Harvey and Boksa
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