In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders

Neuroscience and Biobehavioral Reviews 33 (2009) 1061–1079

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Review

In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders Urs Meyer a,*, Joram Feldon a, S. Hossein Fatemi b,c,d a

Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology (ETH) Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, USA c Department of Pharmacology, University of Minnesota Medical School, 310 Church St. SE, Minneapolis, MN 55455, USA d Department of Neuroscience, University of Minnesota Medical School, 310 Church St. SE, Minneapolis, MN 55455, USA b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 19 January 2009 Received in revised form 21 April 2009 Accepted 4 May 2009

Based on the epidemiological association between maternal infection during pregnancy and enhanced risk of neurodevelopmental brain disorders in the offspring, a number of in-vivo models have been established in rats and mice in order to study this link on an experimental basis. These models provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, and to explore the critical neuroimmunological and developmental factors involved in shaping the vulnerability to infection-induced neurodevelopmental disturbances in humans. Here, we summarize the findings derived from numerous in-vivo models of prenatal infection and/or immune activation in rats and mice, including models of exposure to influenza virus, bacterial endotoxin, virallike acute phase responses and specific pro-inflammatory cytokines. Furthermore, we discuss the methodological aspects of these models in relation to their practical implementation and their translatability to the human condition. We highlight that these models can successfully examine the influence of the precise timing of maternal immune activation, the role of pro- and anti-inflammatory cytokines, and the contribution of gene–environment interactions in the association between prenatal immune challenge and postnatal brain dysfunctions. Finally, we discuss that in-vivo models of prenatal immune activation offer a unique opportunity to establish and evaluate early preventive interventions aiming to reduce the risk of long-lasting brain dysfunctions following prenatal exposure to infection. ß 2009 Elsevier Ltd. All rights reserved.

Keywords: Animal model Autism Behavior Cross-fostering Cytokines Genes Immune system Infection Neurodevelopment Pregnancy Prevention Schizophrenia

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General experimental designs of prenatal immune activation models . . . . . . . . . . . . . . . 2.1. Timed pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Postnatal cross-fostering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Litter effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Specificity and intensity of the immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Viral and bacterial infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. PolyI:C and LPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Specific pro-inflammatory cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Influence of dosing and administration routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phenotyping strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. The relevance of multi-task approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The relevance of the postnatal age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. The relevance of sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Studying the impact of the precise timing of maternal infection . . . . . . . . . . . . . . . . . . . 5.1. Exploring the neurodevelopmental impact of the precise timing in experimental

* Corresponding author. Tel.: +41 44 655 7403; fax: +41 44 655 7203. E-mail address: [email protected] (U. Meyer). 0149-7634/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2009.05.001

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5.2. Methodological considerations. . . . . . . . . . . . . . . . Studying gene–environment interactions . . . . . . . . . . . . . Studying early interventions and preventive treatments. 7.1. Preconceptional treatments . . . . . . . . . . . . . . . . . . 7.2. Acute interventions during pregnancy. . . . . . . . . . 7.3. Early preventive drug treatment in the offspring . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Disturbances directed at the maternal host during pregnancy can lead to direct physiological changes in the fetal environment and negatively affect the normal course of early brain development in the offspring (Rees and Harding, 2004; Rees and Inder, 2005). This can have long-lasting consequences for the development of postnatal brain dysfunctions, in which the primary cerebral insult or pathological process occurs during early brain development and long before the illness is clinically manifest. Two prominent examples of such neuropathological outcomes are schizophrenia and autism: both disorders seem to be associated with aberrations in early neurodevelopmental processes caused by a combination of environmental and genetic factors, which predispose the organism to long-lasting neuropathology and psychopathology (Weinberger, 1987; Murray et al., 1991; Rapoport et al., 2005; Ross et al., 2006; DiCicco-Bloom et al., 2006). Accumulating evidence suggests that maternal infection during pregnancy is one of the relevant environmental risk factors of neurodevelopmental brain dysfunctions in the offspring. Numerous retrospective epidemiological studies have found a higher risk of schizophrenia and related psychotic disorders in offspring born to mothers with viral or bacterial infections during early-to-middle stages of pregnancy (reviewed in Brown and Susser, 2002; Fatemi, 2005; Brown, 2006, 2008; Patterson, 2007; Boksa, 2008). A similar (albeit less established) link has also been found for autism (Chess, 1971; Arndt et al., 2005). Importantly, the establishment of prospective epidemiological approaches has provided clear serologic evidence for at least some of the infectious agents implicated in the prenatal infectious etiology of schizophrenia (Brown et al., 2004a,b, 2005; Mortensen et al., 2007). Moreover, some of the reported effects indentified by prospective epidemiological approaches appear to be relatively strong in magnitude (see, e.g., Brown et al., 2004a). Hence, even though all epidemiological studies are observational in nature (and thus cannot prove causality), it is possible to comment on casual interferences from recent prospective epidemiological findings demonstrating markedly enhanced risk of schizophrenia and related disorders following serologically documented prenatal exposure to infection. In parallel to the establishment of prospective epidemiological research designs, a number of in-vivo models of prenatal immune activation in rats and mice have been developed in order to test the hypothesis of causality in human epidemiological associations. Using behavioral, cognitive and pharmacological paradigms relevant to the phenotypic characterization of schizophreniaand autism-like symptoms (Table 1), these rodent models have provided substantial evidence for a causal relationship between prenatal exposure to numerous infectious and/or immune activating agents and the emergence of multiple brain dysfunctions in adult life. The spectrum of the functional deficits induced by the various prenatal immunological insults is summarized in Table 2. Many of the functional deficits induced by prenatal immune challenge in rats and mice are implicated in some of the

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most critical phenotypes of schizophrenia and autism, including sensorimotor gating deficiency, abnormalities in selective associative learning, working memory impairment, enhanced sensitivity to psychostimulant drugs, and deficits in social behavior (Tables 1 and 2). Furthermore, some of the behavioral and cognitive deficits induced by in-utero immune challenge in rats and mice can be normalized by acute and/or chronic antipsychotic drug treatment (Borrell et al., 2002; Shi et al., 2003; Zuckerman et al., 2003; Zuckerman and Weiner, 2005; Ozawa et al., 2006; Romero et al., 2007), suggesting that the prenatal immune activation models also fulfill predictive validity for psychosisrelated dysfunctions. In addition to the functional impairment, parallel morphological and neurochemical analyses in rats and mice have demonstrated a wide variety of neuroanatomical and neurochemical changes in the adult central nervous system (CNS) following prenatal exposure to infection and/or inflammation. These include pre- and postsynaptic changes in various neurotransmitter systems such as the central dopamine (DA), gaminobutyric acid (GABA), and glutamate (GLU) systems, together with alterations in neuronal and glial cell number, structure and positioning (Table 3). The aim of the present article is to describe the general design of prenatal immune activation models in rats and mice and to discuss their value in the basic research of prenatal infectious etiologies of neurodevelopmental brain disorders, particularly schizophrenia and autism. Thereby, we highlight methodological considerations and emphasize the advantages and disadvantages of specific experimental models. In addition, we illustrate how in-vivo rodent models of prenatal immune activation can be successfully used to explore critical neuroimmunological and developmental factors involved in shaping the vulnerability to infection-induced neurodevelopmental disturbances in humans. A special emphasis is placed on the influence of the precise timing of maternal immune activation, the role of pro- and anti-inflammatory cytokines, and the relevance of gene–environment interactions in the association between prenatal immune challenge and postnatal brain dysfunctions. Finally, we discuss the unique opportunities of in-vivo rodent models to evaluate early preventive interventions aimed at reducing the risk of long-lasting brain dysfunctions following prenatal exposure to infection. 2. General experimental designs of prenatal immune activation models 2.1. Timed pregnancy Prenatal immune activation models in rats and mice are designed to study the effects of maternal exposure to infection and/or immune activating agents on abnormal brain and behavioral development in the offspring. A frequent requirement is that the maternal and/or fetal immune systems are activated only within specific stages of gestation (see subsequent sections). This requires that the immunological manipulation is conducted in timed-pregnant animals in order to control the prenatal timing.

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Table 1 A sample of rodent behavioral and pharmacological paradigms for the phenotypic characterization of neuropsychological and neurochemical abnormalities implicated in schizophrenia and autism. Neuropsychological and/or neurochemical domains

Experimental paradigm

Symptoms in schizophrenia

Symptoms in autism

References

Sensorimotor gating

Prepulse inhibition of the acoustic startle reflex

Impaired

Impaired

Braff et al. (2001), Swerdlow et al. (2000), Perry et al. (2007)

Attentional control of selective associative learning

Latent inhibition

Impaired in patients with acute positive symptoms; abnormally enhanced in patients with marked negative symptoms Reduced especially in acutely ill patients

Not determined

Feldon and Weiner (1992), Moser et al. (2000), Weiner (2003), Lubow (2005) Jones et al. (1992), Moran et al. (2003, 2008)

Kamin blocking

Not determined

Sustained attention and vigilance

5-Choice serial reaction time test

Impaired in patients with schizophrenia and their non-psychotic first-degree relatives

Impaired

Laurent et al. (1999, 2000), Elveva˚g et al. (2000), Allen and Courchesne (2001), Birkett et al. (2007)

Working memory

Delayed non-match to sample/position Radial arm maze Morris watermaze Y-maze

Impaired

Impaired

Goldman-Rakic (1994), Castner et al. (2004), Hill (2004)

Social behavior

Social interaction and recognition tests

Reduced especially in patients with negative symptoms

Reduced

McGlashan and Fenton (1992), Lord et al. (2000), Moy et al. (2006), Crawley (2007)

Stereotypy and perseverative behavior

Open field exploration test Holeboard exploration test Discrimination reversal learning

Stereotypic behavior; abnormally enhanced behavioral flexibility in patients with marked positive symptoms (switching behavior); behavioral and/or cognitive inflexibility in patients with marked negative symptoms

Restricted repetitive behavior; perseverative behavior

Lord et al. (2000), Moy et al. (2006), Crawley (2007)

Dopamine-associated neurotransmission

Behavioral reaction to amphetamine In-vivo microdialysis following systemic amphetamine challenge

Increased sensitivity to dopamine-stimulating drugs; enhanced striatal dopamine release

No major changes in dopamine-associated neurotransmission

Lieberman et al. (1987), Laruelle et al. (1996, 2003), Lam et al. (2006)

Glutamate-associated neurotransmission

Behavioral reaction to ketamine, dizocilpine and phencyclidine In-vivo microdialysis following systemic treatment with ketamine, dizocilpine and phencyclidine

Increased sensitivity to NMDA-receptor-blocking drugs; NMDA-receptor hypofunctions

Enhanced glutamatergic signaling; increased AMPA- (but not NMDA-) receptor expression

Carlsson et al. (2001), Purcell et al. (2001), McDougle et al. (2005), Eyjolfsson et al. (2006)

Many professional breeding facilities offer timed-pregnant rats and mice. However, purchasing such animals for immediate use in prenatal immune activation models should clearly be avoided, because the shipment of animals in general, and during pregnancy in particular, is associated with considerable stress for the animals. Prenatal exposure to stress can lead to significant changes in the offspring’s brain and behavioral development (Koenig et al., 2002, 2005; Sullivan et al., 2006; Fumagalli et al., 2007; Mueller and Bale, 2007, 2008; Kinney et al., 2008). This may introduce a significant confound to the anticipated outcomes in prenatal immune activation models, and it may further complicate the interpretation of prenatal immune activation effects on the offspring. It is thus highly recommended that the animals intended for prenatal immune activation experiments are bred at the same facilities in which the final readouts of the experiments will be evaluated. One simple way to obtain timed-pregnant rats and mice is to subject male and female breeders to a timed-mating procedure and then verify successful copulation by the presence of vaginal plugs (see Fig. 1). It is worth emphasizing that female mice get (temporarily) anestrous when grouped unisexually for a

prolonged period (Whitten, 1957; Gangrade and Dominic, 1983, 1984). Induction of the estrous cycle in female mice is therefore needed before the commencement of the timed-mating procedure. This can be achieved by housing up to four female mice in a partitioned cage with one male, thus allowing olfactory but not physical contact between male and female animals (Fig. 1). According to the ‘‘Whitten effect’’ (Whitten, 1957; Gangrade and Dominic, 1983, 1984), 3 days of partitioned housing of male and female mice is sufficient exposure to male pheromones to induce and synchronize the estrous cycle in females. Thereafter, male and female mice can be brought together and successful mating can be verified by the presence of a vaginal plug (Fig. 1). The ‘‘Whitten effect’’ (i.e., the synchronization of the estrous cycles of females exposed to the pheromones of males) also occurs in rats, but it is not as pronounced as in mice. 2.2. Postnatal cross-fostering Many manipulations during pregnancy, including maternal immune activation, are known to alter post-partum maternal

Species

Gestation period

Functional brain abnormalities in offspring born to immune-challenged mothers Prepulse inhibition

Latent inhibition

Social behavior

Exploratory behavior

Working memory

Sensitivity to DA-R agonists

Sensitivity to NMDA-R agonists

Influenza

Mouse

Early/middle

#

ND

#

#

ND

ND

"

PolyI:C

Mouse Mouse Mouse Rat

Early/middle Middle ! late Late Middle/late

# # #

# ND #

# ND ND ND

# ND ND ND

# # # ND

" " " "

" ND " "

LPS

Rat Rat Rat Mouse

Early ! late Middle Late Late

# # # ND

ND ND ND ND

ND ND ND #

ND ND ND -

ND ND ND ND

ND ND " ND

ND ND ND ND

IL-6

Mouse

Early/middle

#

#

#

#

ND

ND

ND

Turpentine

Rat

Middle

#

ND

ND

ND

ND

ND

ND

The table specifies the precise timing of the prenatal maternal immune challenge as well as the rodent species used for the experimental investigations. Downward and upward arrows indicate an impairment or enhancement of the particular phenotype, respectively; the hyphens indicate that no significant changes were detected relative to the corresponding control treatment. ND = not determined; DA-R = dopamine receptor; NMDA-R = N-methyl-Daspartate receptor. The data are from Borrell et al. (2002), Shi et al. (2003), Zuckerman et al. (2003), Zuckerman and Weiner (2003, 2005), Fortier et al. (2004a, 2007), Golan et al. (2005), Meyer et al. (2006a,b,c, 2008a,b,c, in press-b), Ozawa et al. (2006), Romero et al. (2007, in press), Smith et al. (2007), Makinodan et al. (2008), Wolff and Bilkey (2008).

Table 3 Summary of morphological brain abnormalities relevant to schizophrenia and autism as identified in various in-vivo rodent models of prenatal immune activation. The models are based on prenatal exposure to human influenza virus, the viral mimic polyriboinosinic–polyribocytidilic acid (PolyI:C), the bacterial endotoxin lipopolysaccharide (LPS), and the pro-inflammatory cytokine interleukin-6 (IL-6). Immunogen

Species

Gestation period

Morphological brain abnormalities in offspring born to immune-challenged mothers Cortico-/neurogeneis

Pyramidal cells

Purkinje cells

Gliosis

Reelin

PV

TH

GABAA-R

DA-R

NMDA-R

Influenza

Mouse

Early/middle

#a,b

Increased density; atrophy

#c

"a,b

#a,b

ND

ND

ND

ND

ND

b

c

a,b

a

d

b,e

d

a

PolyI:C

Mouse Mouse Rat

Early/middle Late Middle/late

# #b ND

Pyknotic

# ND ND

ND

# #a,b ND

# #a,b ND

" ND ND

" "b ND

" # ND ND

#b ND

LPS

Rat Mouse

Early ! late Late

ND ND

ND Increased density; shrinkage

ND ND

"c ND

ND ND

ND ND

"d ND

ND ND

ND ND

ND ND

IL-6

Rat Rat

Early ! late Middle ! late

ND ND

Pyknotic; loss Pyknotic; loss

ND ND

"b "b

ND ND

ND ND

ND ND

"b

ND ND

"b

The table specifies the precise timing of the prenatal maternal immune challenge as well as the rodent species used for the experimental investigations. Downward and upward arrows indicate an impairment or enhancement of the particular phenotype, respectively; the hyphens indicate that no significant changes were detected relative to the corresponding control treatment. ND = not determined; DA-R = dopamine receptor; GABAA-R = g-aminobutyric acid receptor subtype A; NMDA-R = N-methyl-D-aspartate receptor; PV = parvalbumin; TH = tyrosine hydroxlyase. The data are from Fatemi et al. (1998a,b, 1999, 2000, 2002a,b, 2004, 2008a,b), Borrell et al. (2002), Zuckerman et al. (2003), Golan et al. (2005), Meyer et al. (2006b, 2008b,c), Nyffeler et al. (2006), Samuelsson et al. (2006), Romero et al. (in press). a Frontal cortex. b Hippocampus. c Cerebellum. d Striatum. e Amygdala.

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Immunogen

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Table 2 Summary of behavioral, cognitive and pharmacological dysfunctions relevant to schizophrenia and autism as identified in various in-vivo rodent models of prenatal immune activation. The models are based on prenatal exposure to human influenza virus, the viral mimic polyriboinosinic–polyribocytidilic acid (PolyI:C), the bacterial endotoxin lipopolysaccharide (LPS), the pro-inflammatory cytokine interleukin-6 (IL-6), and the locally acting inflammatory agent turpentine.

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Fig. 1. Synchronization of estrous cycle and verification of successful mating. (A) The photograph shows a standard housing cage for mice, with a partitioning wall allowing olfactory but not physical contact between male (at rear) and female (in front) mice. The grid top, water bottles and food container have been removed for better visibility of the partitioning wall. Prior to the mating procedure, partitioned housing of male and female mice can be used to induce and synchronize the estrous cycle in (temporarily) anestrous female mice by exposure to male pheromones. This enhances fertility in female mice that were grouped unisexually for a prolonged period. (B) Successful mating can be verified by the presence of a vaginal plug (copulatory plug). The photograph shows a female C57BL/6 mouse with a copulatory plug occluding the opening of the vagina (indicated by the white arrow).

behavior (Moore and Power, 1986; Meek et al., 2001; Patin et al., 2002; Smith et al., 2004; Schwendener et al., 2009). Disruption of the intricate mother–infant relationship resulting from immunological stress during pregnancy may thus confer additional risk for the offspring to develop brain pathology in later life (Meyer et al., 2006c, 2008b; Schwendener et al., 2009). This may readily undermine the conclusions as to whether prenatal and/or postnatal maternal effects on the offspring account for brain and behavioral abnormalities emerging in offspring born to immune-challenged mothers. One effective way to dissect the relative contributions of prenatal and postnatal maternal factors is to implement a postnatal cross-fostering procedure (Fig. 2). In doing so, one has to keep in mind that mother–infant interactions are reciprocal (Fleming et al., 1999; Walker et al., 2004). The rearing mother’s care influences the physiological and neurobehavioral development of the offspring, while in turn the offspring’s affiliative behavior and demands critically determine how competent maternal care will be. In order to ensure that each surrogate mother is exposed to similar affiliative behaviors and demands originating from the pups, each surrogate mother should concomitantly raise pups of both the prenatal treatment and control conditions. This can be achieved by simultaneously fostering prenatally immune challenged and control pups to either a surrogate mother that had experienced immune challenge during pregnancy, or to a sham-treated control surrogate mother (see Fig. 2). Such simultaneous cross-fostering designs are devoid of possible interpretative problems related to issues in attributing putative changes in post-partum maternal behavior, either to the immunological insult encountered during pregnancy, or to possible differences in the affiliative behavior displayed by neonates born to immune-challenged and control-treated mothers (Schwendener et al., 2009).

inflating real effect sizes (Haseman and Hogan, 1975; Holson and Pearce, 1992). The magnitude of litter effects depends on the relative contribution of genetic and common environmental factors to variation in the variable of interest (Zorrilla, 1997). Hence, an important implication for developmental research using rodent species is that the experimental design should account for litter effects. One simple way to circumvent the

2.3. Litter effects Most rodents are multiparous species and normally produce litters of up to eight to twelve offspring. Compared with pups from other litters, littermates are more likely to share genetic and epigenetic similarities, and are exposed to more similar antenatal (e.g., in-utero physiology) and postnatal (e.g., maternal physiology and behavior) environments. Littermates are therefore interdependent, and can produce pervasive and persistent litter effects (Zorrilla, 1997), leading to false negative findings, and possibly

Fig. 2. General design of existing in-vivo models of maternal immune activation in rats and mice. Pregnant animals are exposed to infectious and/or immune activating agents (e.g., human influenza virus, virus-specific double-stranded RNA, bacterial endotoxin, or specific pro-inflammatory cytokines) or corresponding sham treatment (most often in the form of administration of the vehicle substance) at certain stages of gestation. Offspring born to immune-challenged and shamtreated mothers can then be cross-fostered simultaneously to either a surrogate mother that had experienced immunological challenge during pregnancy, or to a sham-treated control surrogate mother. Postnatal cross-fostering designs help to dissect the relative contribution of prenatal and postnatal maternal effects on the offspring.

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problem would be to include only one offspring from each experimental litter in the subsequent structural and functional investigations. In this case, the number of offspring per treatment group is identical to the number of treated mothers in each experimental group, and the offspring can easily be treated as independent observations in the statistical analyses. However, this approach is often practically and ethically not feasible, because it requires the experimenter to include a large number of pregnant mothers in each experimental condition. Furthermore, it leads to the loss of potentially important information, including information about within-litter variability. The alternative of including more than one offspring per litter in the experimental investigations warrants the use of appropriate statistical methods in order to avoid possible confounds arising from litter effects. As described in detail elsewhere (Zorrilla, 1997), one reasonable statistical model would be to treat litter as a covariate nested under treatment condition. Alternatively, one may also consider the use of statistical models which do not assume that littermates are independent observations (see Zorrilla, 1997). Whatever statistical model is used, we recommend an experimental design in which the offspring stem from at least six to eight mothers per treatment condition. This helps to achieve a better representation of the between-subjects variability associated with natural differences in the maternal immune response to a particular immune-stimulating agent, and to obtain reliable and meaningful effects on brain and behavior in the resulting offspring. 3. Specificity and intensity of the immune response There are numerous ways by which the maternal immune system can be challenged during pregnancy. Depending on the key questions to be addressed, the immunological challenge may be in the form of exposure to specific viral or bacterial pathogens, viralor bacterial-like immune activating agents, or individual proinflammatory cytokines (Fig. 2). Different infectious and/or immune activating agents induce distinct but partly overlapping immune responses in the periphery, and they may exert differing neurodevelopmental effects in the CNS (reviewed in Meyer et al., 2007, in press-a). Therefore, maternal exposure to distinct immune-activating stimuli may also significantly influence the nature and severity of the long-term brain and behavioral sequelae in the offspring. Comparing the neurodevelopmental impact of prenatal exposure to distinct infectious and/or immune activating agents thus facilitates the identification of the critical molecular mediators of the link between prenatal immune challenge and the emergence of postnatal brain dysfunctions. 3.1. Viral and bacterial infections Based on the reported association between prenatal influenza infection and adult schizophrenia (Mednick et al., 1988; Wright et al., 1995; Sto¨ber et al., 2002; Limosin et al., 2003; Brown et al., 2004a), Fatemi and colleagues have pioneered an experimental animal model of prenatal exposure to human influenza virus in mice (Fatemi et al., 1998a,b, 1999, 2000, 2002a,b, 2004, 2008a,b; Shi et al., 2003). In this model, pregnant mice are infused intranasally with a sublethal dose of a neurotropic strain of human influenza virus, and the long-term brain and behavioral effects are then evaluated in the resulting offspring relative to control offspring born to sham-treated mothers. In a series of experiments, Fatemi and co-workers have demonstrated that maternal influenza infection leads to a variety of neuropathological signs in the offspring’s brains postnatally, some of which are critically implicated in the neuropathology of schizophrenia and autism (Fatemi et al., 1998a,b, 1999, 2000, 2002a,b, 2004, 2008a,b; for a summary see Table 3). In addition to the identified

morphological alterations (Table 3), maternal influenza infection in mice leads to persistent changes in the expression levels of numerous genes in the offspring’s CNS (Fatemi et al., 2005, 2008a,b). Furthermore, prenatal exposure to influenza virus in mice also induces a set of behavioral and pharmacological changes in adulthood, which are related to some of the critical abnormalities in individuals with schizophrenia and autism (Shi et al., 2003). Hence, the prenatal influenza model in mice is highly suitable for experimental investigations of the human epidemiological association between prenatal exposure to influenza infection and enhanced risk of these disabling brain disorders in the offspring. This model enjoys a high level of construct and face validity for schizophrenia- and autism-like pathology, and it accounts for one of the well-known environmental factors implicated in the infectious etiology of these disorders. Significant changes in postnatal brain structure and function have also been observed in rats and mice born to mothers exposed to other viral or bacterial infections, including Theiler’s encephalomyelitis virus (Abzug and Tyson, 2000), Campylobacter rectus (Offenbacher et al., 2005; Yeo et al., 2005), and Escherichia coli (Rodts-Palenik et al., 2004; Pang et al., 2005). However, in contrast to the influenza infection model in mice, the long-term neurobehavioral consequences of prenatal exposure to these pathogens have so far been explored only marginally. Further studies are thus needed in order to test whether prenatal exposure to different viral or bacterial pathogens may induce similar neuropathology in the offspring, or whether the specificity of the pathogen may critically determine the nature of the long-term brain and behavioral effects in the offspring. 3.2. PolyI:C and LPS The structural and functional brain abnormalities emerging in offspring of mothers exposed to viral or bacterial infections during pregnancy may be accounted for by effects that are specific to the immune responses to the individual viral or bacterial pathogen. This may include direct effects in the fetal brain such as presence of virulent pathogens and viral or bacterial antibodies in fetal brain tissue. Alternatively, the detrimental long-term effects on brain and behavior may be mediated indirectly by effects associated with the activation of the maternal immune system. One straightforward experimental approach to explore this issue directly is to evoke antiviral-like or antibacterial-like immune responses in the mother without using viral or bacterial pathogens. Two of the best established models are based on maternal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), and the synthetic analogue of double-stranded RNA, polyriboinosinic:polyribocytidilic acid (PolyI:C). LPS is recognized by toll-like receptor (TLR) 2 and TLR4, whereas PolyI:C is recognized primarily by TLR3 (Alexopoulou et al., 2001; Triantafilou and Triantafilou, 2002; Takeuchi and Akira, 2007). TLRs are a class of pathogen recognition receptors, which recognize invariant structures present on virulent pathogens. Upon binding to TLRs, LPS and PolyI:C both stimulate the production and release of many pro-inflammatory cytokines, including interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a (Kimura et al., 1994; Fortier et al., 2004b; Meyer et al., 2006a,b,c). In addition, PolyI:C is a potent inducer of the type I interferons IFN-a and IFN-b (Alexopoulou et al., 2001; Takeuchi and Akira, 2007). Therefore, whereas LPS exposure leads to a cytokine-associated innate immune response that is typically seen after infection with gram-negative bacteria (Triantafilou and Triantafilou, 2002), administration of PolyI:C mimics the acute phase response to viral infection (Traynor et al., 2004). There are several advantages of using antiviral-like (PolyI:C) or antibacterial-like (LPS) immunogens instead of viral or bacterial pathogens in in-vivo rodent models of prenatal immune activation.

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Firstly, unlike viral or bacterial pathogens, PolyI:C and LPS can be easily handled without stringent biosafety precautions. Secondly, the intensity of the cytokine-associated immune responses can be easily controlled by appropriate dose–response studies (Shi et al., 2003; Meyer et al., 2005; Cunningham et al., 2007). Thirdly, PolyI:C- or LPS-induced immunological challenges in rodents are time-limited, ranging from 24 to 48 h depending on the precise dose used (Meyer et al., 2005; Cunningham et al., 2007). This allows precise setting of the times of the maternal immune activation corresponding to specific periods of fetal development. This aspect is particularly relevant when prenatal immune activation models are designed with the aim of exploring the impact of the precise timing in the association between prenatal immune challenge and postnatal brain dysfunctions (see below). Finally, maternal exposure to LPS or PolyI:C can alter pro- and antiinflammatory cytokine levels in the three relevant compartments of the maternal–fetal interface of rodents, namely the placenta, the amniotic fluid, and the fetus, including the fetal brain (Cai et al., 2000; Urakubo et al., 2001; Gayle et al., 2004; Gilmore et al., 2005; Ashdown et al., 2006; Meyer et al., 2006b, 2008a). Importantly, the changes in fetal cytokine expression occur without penetration of the immune-stimulating agent from the maternal system to the fetal environment (Ashdown et al., 2006). This is an important feature of the PolyI:C-and LPS-based models, because it allows one to study effects on the offspring that are mediated indirectly by activation of the maternal immune system. Compared to infection models using viral or bacterial pathogens, one limitation of the LPS and PolyI:C models of immune activation is that they do not readily mimic the precise immunological insults occurring in the human environment. That is, they fall short in modeling the full spectrum of immune responses normally induced by viral or bacterial exposure. Rather, they mimic especially the cytokine-associated bacterial- or virallike acute phase responses in the maternal host, and thereafter, in the fetal environment. However, this aspect of the LPS- or PolyI:Cbased immune activation models is helpful in order to test specifically whether imbalances in maternal and/or fetal cytokine levels may be one of the crucial mediating factors in the link between maternal infection and emergence of brain and behavioral pathology in the offspring. As extensively reviewed elsewhere (Nawa and Takei, 2006; Meyer et al., 2007, in press-a; see also Tables 2 and 3), numerous behavioral, neurochemical and morphological abnormalities have been detected in adult mice and rats following maternal gestational exposure to LPS (Borrell et al., 2002; Fortier et al., 2004a, 2007; Golan et al., 2005; Romero et al., 2007, in press) or PolyI:C (Shi et al., 2003; Zuckerman et al., 2003; Zuckerman and Weiner, 2003, 2005; Meyer et al., 2005, 2006a,b,c, 2008a,b,c, in press-a,b; Ozawa et al., 2006; Makinodan et al., 2008; Winter et al., 2009; Wolff and Bilkey, 2008). At least some of the LPS- and PolyI:C-induced brain and behavioral pathologies are largely identical to those observed in offspring born to influenza-infected mothers, including deficiency in prepulse inhibition, impairments in spatial exploration, and reduced cortical expression of Reelin (see Tables 2 and 3). This indeed suggests that activation of the maternal immune system in the absence of specific virulent pathogens is sufficient to induce significant changes in the offspring’s brain and behavioral development. Hence, the findings from prenatal immune activation models using LPS or PolyI:C as immunostimualtory agents can be taken as support for the hypothesis that the activation of the maternal immune system in general, and abnormal maternal and/or fetal expression of inflammatory cytokines in particular, plays a key role in the association between maternal infection during pregnancy and enhanced risk in the offspring of developing brain disorders with a neurodevelopmental component, including schizophrenia and

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autism (Gilmore and Jarskog, 1997). However, even though numerous experimental findings underline the importance of abnormal maternal/fetal expression of cytokines in the precipitation of neurodevelopmental defects following maternal infection, several alternative (but not mutually exclusive) mechanisms exist whereby prenatal exposure to infection may bring about changes in brain and behavioral development. A detailed discussion of these alternative mechanisms can be found elsewhere (Meyer et al., 2008c). 3.3. Specific pro-inflammatory cytokines Another valuable experimental approach to delineate the role of cytokine-associated mechanisms in the relationship between prenatal infection and postnatal brain disorders is to treat pregnant animals with specific pro-inflammatory cytokines. This approach has been adopted in the recent studies by Samuelsson et al. (2006) in rats, and by Smith et al. (2007) in mice. These authors have demonstrated that administration with exogenous IL-6 to pregnant animals is sufficient to induce long-lasting structural and functional abnormalities in the adult offspring. Moreover, when IL-6 is eliminated from the maternal immune response by genetic interventions or with IL-6 blocking antibodies, maternal immune challenge by PolyI:C is no longer efficient in inducing behavioral mal-development in the resulting offspring (Smith et al., 2007). Interestingly, prenatal exposure to other proinflammatory cytokines alone, including IL-1b, IFN-g, or TNF-a, appears to be insufficient to precipitate similar behavioral deficits in the adult animals; and co-administration of soluble IL-1b or IFNg receptor antagonist to pregnant dams does not prevent the behavioral deficits caused by prenatal PolyI:C exposure (Smith et al., 2007). This supports the hypothesis that the relationship between prenatal immune activation and postnatal brain dysfunctions is critically dependent on the specificity of cytokineassociated immunological reactions (Meyer et al., 2007, in press-a). Specifically, it appears that the pro-inflammatory cytokine IL-6 assumes a key role in mediating the effects of maternal immune activation on fetal brain development. 3.4. Influence of dosing and administration routes Regardless of the precise model used, the choice of the precise dose and/or administration route of the immune-activating agent may critically influence the anticipated outcomes in the model system. Firstly, exposing pregnant animals to immunological stimulation at high intensity can induce marked fetal mortality and spontaneous abortion (Entrican, 2002), thereby leading to small litter sizes. This problem can be avoided by the use of comprehensive dose–response studies, which facilitate the identification of functionally effective doses that are associated with only minimal fetal mortality (Shi et al., 2003; Meyer et al., 2005). The dose of the particular immunostimulatory agent may also greatly influence cytokine specificity in the maternal and fetal compartments; and this may further interact with the precise gestational stage, at which the immunological challenge is conducted (Fig. 3). The precise pattern of maternal/fetal cytokine responses may, in turn, considerably influence the long-term brain and behavioral effects in the offspring, given that cytokine specificity is one of the critical factors in the association between prenatal immune challenge and emergence of postnatal brain dysfunctions (Smith et al., 2007; Meyer et al., 2008a). We would thus recommend the assessment of cytokine responses in the maternal and fetal systems following a specific maternal immunological manipulation during pregnancy. This would readily facilitate the comparison between experimental findings obtained in different prenatal immune activation models, and

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Fig. 3. The specificity of fetal brain cytokine responses to maternal infection is dependent on the immune stimulus intensity as well as the precise gestational timing. (A) The graph depicts the effects of maternal PolyI:C exposure during pregnancy on the fetal brain levels of the pro- and anti-inflammatory cytokines IL-6 and IL-10, respectively. Pregnant C57BL/6 mice on gestation day (GD) 9 or GD17 were injected with either a low (2 mg/kg, i.v.; 2 mg POL) or high (8 mg/kg, i.v.; 8 mg POL) dose of PolyI:C, or with corresponding vehicle (VEH; pyrogen-free isotonic 0.9% NaCl) solution. Cytokine levels were measured in the fetal brains 3 h post-treatment using a multiplexed particlebased flow cytometric cytokine assay as described in detail elsewhere (Meyer et al., 2006b, 2008a). The fetal brain IL-6 response to maternal immune challenge is attenuated in GD17-fetuses compared to GD9-fetuses, and the brain contents of the anti-inflammatory cytokine IL-10 are generally increased in fetuses derived from VEH- or PolyI:Ctreated GD17 mothers relative to GD9 mothers. Symbols (*), (**), and (***) refer to a statistical significance of P < 0.05, P < 0.01, and P < 0.001, respectively, based on Fisher’s post hoc comparisons between the six experimental groups following presence of a significant prenatal treatment  gestational stage interaction [F(2,59) = 4.54, P < 0.05] in the 3  2 (prenatal treatment  gestational stage) ANOVA of IL-6 levels. Symbol (#) refers to a statistically significant difference of P < 0.001 between GD9 and GD17 fetuses associated with the significant main effect of gestational stage [F(1,59) = 30.28; P < 0.001] in the corresponding ANOVA. Symbol (§) refers to a statistically significant difference of P < 0.05 between 8 mg POL fetuses and 2 mg POL or VEH fetuses, based on Fisher post hoc comparison between the three prenatal treatment conditions following presence of a significant main effect of prenatal treatment [F(2,59) = 3.70, P < 0.05] in the initial ANOVA of IL-10. (B) The graph depicts the effects of maternal PolyI:C administration on the fetal brain balance between pro- and anti-inflammatory cytokines expressed as IL-6/IL-10 ratio. Maternal immunological stimulation by PolyI:C increases the brain ratio of IL-6/IL-10 in fetuses derived from mothers in early/middle gestation (GD9) compared to corresponding control treatment at this gestational stage. This demonstrates a shift toward enhanced pro-inflammatory cytokine signaling after prenatal immune challenge during early/middle fetal development. In contrast, maternal PolyI:C exposure at these immune stimulus intensities is not efficient in significantly increasing the IL-6/IL-10 ratio in the fetal brain in late gestation (GD17). Symbol (**) refers to a statistical significance of P < 0.01, based on Fisher’s post hoc comparisons between the six experimental groups following presence of a significant prenatal treatment  gestational stage interaction [F(2,59) = 7.26; P < 0.01] in the 3  2 (prenatal treatment  gestational stage) ANOVA of the IL-6/IL-10 ratio. N(GD9VEH) = 10; N(GD9–2 mg POL) = 8; N(GD9–8 mg POL) = 7; N(GD17–VEH) = 13; N(GD17–2 mg POL) = 15; N(GD17–8 mg POL) = 12. Fetuses were derived from six mothers in each treatment condition and gestational stage. All values are means  SEM.

between similar models established in different rodent species such as rats and mice. With the exception of respiratory infections such as influenza, most immune-activating agents can be administered effectively via the intraperitoneal (i.p.), intravenous (i.v.), or subcutaneous (s.c.) route. Many research groups chose i.p. administration because it is a relatively quick and easy procedure to perform. However, i.p. administration of substances to pregnant rodents needs special caution so as not to introduce injuries to the uterine horns and placental tissue. This issue becomes particularly relevant in models in which the maternal immunological manipulation is conducted in late gestation. This potential problem can be circumvented by the use of i.v. injections (e.g., at the tail vein) or s.c. injections (e.g., at the neck). It needs to be emphasized that in addition to the dose, the administration route can also critically influence the nature and intensity of the immunological reaction. In general, considerably lower doses of immune-stimulating agents are necessary to obtain the functional and structural effects in i.v.- compared to i.p.-based immune activation models (for a comparison in mice, see, e.g., Shi et al., 2003 and Meyer et al., 2005). Sometimes it is wished to explore the impact of sub-chronic or chronic maternal immune activation on brain structures and functions in the offspring (see, e.g., Borrell et al., 2002; Ozawa et al., 2006; Romero et al., 2007, in press). One way to activate the maternal immune system sub-chronically or chronically is to subject pregnant animals to repeated immunogen exposures. Notably, the amount of experienced stress resulting from repeated injections is considerably higher than single administration protocols. The relative contribution of maternal stress is thus arguably more pronounced in chronic relative to acute immune

activation models. In addition, repeated administration of the same substance can result in immune tolerance, a phenomenon in which the immune-stimulating agent loses its efficacy to elicit the relevant immune response. One particular example is LPS tolerance: Rodents display a markedly diminished pro-inflammatory cytokine reaction after repeated LPS treatment compared to the reaction elicited by the first exposure (Fan and Cook, 2004; Medvedev et al., 2006). 4. Phenotyping strategies 4.1. The relevance of multi-task approaches Prenatal immune activation models do not rely on any specific presumption of a particular disorder’s neuronal substrates, nor are they are based on any specific neurological or pathophysiological features of the disorder. Instead, they are designed to interfere with early neurodevelopmental processes long before the onset of multiple brain and behavioral abnormalities in peri-adolescent and adult life. Since infection-induced disruption of early brain development can be expected to result in wide-ranging neurodevelopmental sequelae, the full spectrum of resulting functional brain deficits is best captured through the use of multi-task approaches involving a compressive array of behavioral, cognitive and pharmacological assays (Meyer et al., 2005). In addition, the use of parallel neurophysiological techniques may yield important insights into the relative contribution of discrete neuronal populations to functional impairment in complex forms of behavior and cognition (Lowe et al., 2008). The use of multi-task approaches in the phenotypic characterization of the long-term effects of prenatal immune activation

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seems necessary for several reasons. Firstly, a given behavioral trait is typically regulated by multiple interconnected brain structures, and disturbances at many sites within a complex neuronal circuitry can give rise to a similar pathological phenotype. Likewise, abnormalities in one particular brain area or neurotransmitter system are likely to have an impact on a wide range of behavioral, cognitive and pharmacological functions (Arguello and Gogos, 2006; Crawley, 2007, 2008). Given that infection-induced interference with early brain development can lead to abnormalities in multiple brain areas and neurotransmitter systems (Table 3), it seems unlikely that a specific pathological phenotype at the functional level is accounted for by dysfunctions in isolated brain structures. Rather, interactions and additive effects between different neuronal dysfunctions in multiple brain areas are likely to be involved in the precipitation of specific forms of behavioral disturbances following prenatal exposure to infection/inflammation (Meyer and Feldon, in press). For example, adult mice prenatally exposed to PolyI:C-induced immune challenge in late gestation display a pronounced GABAergic deficit in the prefrontal cortex together with concomitant GABAergic and glutamatergic abnormalities in the hippocampus (Meyer et al., 2008c). In contrast, early/middle prenatal immune challenge leads to prefrontal cortical GABAergic deficits without markedly affecting the hippocampal glutamatergic system. Both the prefrontal cortex and hippocampus are known to play crucial roles in diverse forms of learning and memory, including working memory (GoldmanRakic, 1991, 1994; Moser et al., 1993; Bannerman et al., 1999; Broersen, 2000; Lewis et al., 2005). Importantly, in addition to the dissociation of the long-term effects of early/middle and late prenatal immune challenge on prefrontal and hippocampal structures, the efficacy of prenatal immune challenge to induce adult working memory deficits in mice also noticeably differs between early/middle and late gestational periods: whereas prenatal immune challenge during early/middle fetal development leads to adult spatial working memory deficits only when the demand on temporal retention is high (Meyer et al., 2005), prenatal immune activation in late gestation induces adult spatial working memory impairments even when the demand on temporal retention is low (Meyer et al., 2008c). One possibility would therefore be that prefrontal (GABAergic) and hippocampal (glutamatergic and GABAergic) dysfunctions have additive effects in the disruption of spatial working memory following prenatal immune challenge in late gestation. According to this interpretation, the concomitant disruption of hippocampal and prefrontal functions may severely impair mnemonic processing after late prenatal immune activation, thereby leading to the emergence of working memory deficits even when the demand on temporal retention is low. On the other hand, the existence of prefrontal pathology in the absence of parallel hippocampal neuropathology may result in working memory deficiency only in situations, in which the demand on temporal retention is high. The use of multi-task approaches also enhances the sensitivity of the specific model to detect relatively modest but potentially important changes in the offspring’s phenotypes. For example, prenatal PolyI:C-induced immune challenge in early/middle gestation in mice (gestation day 9) leads to prepulse inhibition and latent inhibition deficiency in adulthood (Shi et al., 2003; Meyer et al., 2005, 2008c). In contrast, identical PolyI:C treatment in late gestation (gestation day 17) does not significantly influence these phenotypes in mice (Meyer et al., 2008c). If one were only to use the paradigms of prepulse inhibition and latent inhibition in the phenotypic characterization of the long-term consequences of prenatal PolyI:C treatment, one may be left with the impression that late gestational immune challenge (i.e., on and/or subsequent to gestation day 17) in mice is inefficient to induce significant behavioral changes in the adult offspring. However, this is not the

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case: extending the phenotypic characterization to other tests shows that prenatal PolyI:C treatment during late fetal development leads to marked cognitive deficits in adulthood (Meyer et al., 2006b, 2008c). Hence, prenatal immune activation at distinct gestational stages induces different sets of pathological symptoms, which can only be revealed by the use of multiple tests. The influence of the precise timing of prenatal immune challenge on pathological symptom clusters is discussed in more detail in subsequent sections. 4.2. The relevance of the postnatal age Maternal infection during pregnancy induces an immunological lesion to the developing fetal brain. Immunological and morphological investigations in rats and mice show that this lesion is mediated by abnormal fetal brain expression of activated microglia (Nitsos et al., 2006; Hutton et al., 2008; Roumier et al., 2008), proinflammatory cytokines (Cai et al., 2000; Urakubo et al., 2001; Golan et al., 2005; Meyer et al., 2006b, 2008a), and molecular mediators of oxidative stress (Lante´ et al., 2007). Depending on the specificity of the infectious agent, the immunological lesion of the fetal brain may also be associated with the presence of infectious pathogen in fetal brain tissue (Whitley and Stagno, 1997; Aronsson et al., 2002; but see also Shi et al., 2005), which may further negatively affect normal fetal brain development. Since the infection-induced brain lesion is acquired during early stages of brain development, the lesion is likely to be progressive in nature. That is, infection-induced disruption of early fetal brain development may readily affect subsequent postnatal brain development and maturation, and eventually lead to structural and functional brain deficits that are dependent on postnatal maturational processes. This highlights the developmental component in the etiology of abnormal brain structure and function associated with prenatal exposure to infection and/or inflammation. One immediate implication for phenotyping strategies in experimental models of prenatal immune challenge is that the anticipated structural and functional brain abnormalities are noticeable only at specific stages of postnatal development. For example, many of the behavioral, cognitive, and pharmacological abnormalities induced by prenatal exposure to the viral mimic PolyI:C in rats and mice are dependent on post-pubertal maturational processes and thus only emerge in adult but not pre-pubertal subjects (Zuckerman et al., 2003; Zuckerman and Weiner, 2005; Meyer et al., 2006c, 2008b; Ozawa et al., 2006). This maturational delay is indicative of a progression of pathological symptoms from peri-adolescent to adult life, which is consistent with the post-pubertal onset of full-blown psychotic behavior in schizophrenia and related disorders (Weinberger, 1987; Murray et al., 1991; Rapoport et al., 2005; Ross et al., 2006). Moreover, the direction of neuropathological changes induced by prenatal immune challenge can significantly differ between distinct postnatal developmental stages. For example, using a rat model of chronic prenatal immune activation by the bacterial endotoxin LPS, Romero et al. (in press) have recently shown that striatal dopamine levels are significantly decreased in LPS-exposed offspring at peri-adolescent age relative to corresponding control offspring, whilst dopamine levels are significantly enhanced in the striatum of LPS-treated offspring at adult age. Likewise, the detailed morphological analyses by Fatemi and co-workers have highlighted that maternal exposure to human influenza infection in mice leads to maturation-dependent morphological abnormalities in postnatal hippocampal and cortical brain structures (Fatemi et al., 1999, 2002b): whilst pyramidal cell density is significantly increased in influenza-exposed offspring both at birth and in adulthood, non-pyramidal cell density is reduced only in the neonatal period but significantly exceeds normal levels in

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adulthood. Furthermore, prenatal influenza infection in mice leads to macrocephaly in adulthood despite smaller hippocampal and cortical thickness during the neonatal period (Fatemi et al., 1999, 2002b). These morphological abnormalities are paralleled by maturation-dependent changes in the expression of neuronal nitric oxide synthase (nNOS) in the postnatal CNS: Enhanced nNOS expression is observed in influenza-infected offspring during the neonatal (Fatemi et al., 1998a) and peri-adolescent (Fatemi et al., 2000) stage of development, but reduced nNOS expression is noted in the brains of influenza-infected offspring in early adulthood (Fatemi et al., 2000). Together, this highlights that maturationdependent effects need to be taken into account in the interpretation of experimental findings obtained in in-vivo models of prenatal immune activation. 4.3. The relevance of sex Environmental insults targeting the pregnant maternal host may differentially affect brain and behavioral development in male and female offspring. Indeed, numerous experimental studies designed to investigate the impact of prenatal exposure to stressful events provide evidence for critical sex differences in the development of long-term structural and functional brain abnormalities (for a recent review of the rat literature see Weinstock, 2007; for mice see Mueller and Bale, 2007, 2008). However, the relevance of possible sex differences has gained somewhat less attention in experimental models designed to explore prenatal immune activation effects on postnatal CNS structure and function. One reason is that some of the existing studies have focused on the brain and behavioral effects of prenatal immune challenge in male offspring only in order to avoid possible confounds and interpretive problems arising from natural hormonal fluctuations in female offspring (e.g., Meyer et al., 2006c; Fortier et al., 2007; Romero et al., 2007; Wolff and Bilkey, 2008). Nevertheless, there are at least some experimental studies which assessed the long-term neurodevelopmental effects of prenatal immune challenge in both sexes. Interestingly, the majority of these studies did not reveal marked sex-dependent alterations in brain and behavior (e.g., Shi et al., 2003; Zuckerman et al., 2003; Meyer et al., 2005, 2006a,b,c; Ozawa et al., 2006; Romero et al., in press), as opposed to a few studies demonstrating clear sex-dependent effects in at least some brain and behavioral parameters (Meyer et al., 2008b; Schwendener et al., 2009). The former may be indicative of the possibility that male and female offspring may be equally vulnerable to long-term neurodevelopmental abnormalities induced by prenatal immune challenge, whereas the latter would suggest that there may be indeed important sex-dependent effects in the link between prenatal immune activation and emergence of postnatal brain and behavioral disturbances. Additional experimental research is thus clearly warranted in order to address these issues in more detail. Therefore, in addition to the influence of the postnatal age (see above), experimental investigations of the long-term consequences of prenatal immune challenge should also carefully evaluate potential sex-dependent effects by including both male and female subjects in the structural and functional phenotyping. This issue is particularly relevant in the context of complex mental illnesses with a neurodevelopmental component because of the existence of sex-dependent clinical profiles (see, e.g., Flor-Henry, 1990; Aleman et al., 2003). 5. Studying the impact of the precise timing of maternal infection The strength of the association between maternal infection during pregnancy and enhanced risk for neuropsychiatric dis-

orders appears to be critically influenced by the precise prenatal timing. Many of the initial retrospective epidemiological studies found a significant association between maternal viral infection during pregnancy and a higher incidence of schizophrenia in the progeny only when the maternal host was infected in the second trimester of human pregnancy (e.g., Mednick et al., 1988; Wright et al., 1995; Sto¨ber et al., 2002; Limosin et al., 2003). However, recent findings from epidemiological studies using prospectively collected and quantifiable serologic samples indicate that there has been a somewhat excessive emphasis on second trimester infections. For example, there is serologic evidence that influenza infection in early gestation (i.e., in the first trimester of human pregnancy) is associated with the highest risk of schizophrenia in the offspring (Brown et al., 2004a). This thus challenges the prevailing view that influenza infection during the second trimester of pregnancy may confer the maximal risk for the offspring to develop schizophrenia and related disorders in adulthood. A similar conclusion can be drawn from recent epidemiological studies investigating the effects of maternal exposure to rubella infection (Brown et al., 2001), genital and reproductive infections (Babulas et al., 2006), and bacterial infections (Sørensen et al., 2009). The findings from these studies all point to more extensive effects on elevating the risk of schizophrenia if the maternal host is infected early in pregnancy, that is, from the periconceptional period to the end of the first trimester. It follows that the vulnerability to infection-induced neurodevelopmental abnormalities associated with schizophrenia differs between distinct stages of fetal development. However, when comparing the epidemiological data derived from initial retrospective and recent prospective studies, it is still debatable whether there is a time window with maximal vulnerability in the prenatal infectious etiology of this disorder. Furthermore, the relevant neuroimmological and developmental factors underlying the temporal dependency of the link between prenatal infection and risk of neurodevelopmental brain disorders remain largely unidentified thus far. 5.1. Exploring the neurodevelopmental impact of the precise timing in experimental models Animal models of prenatal immune activation provide a powerful tool to examine the critical window hypothesis using prospective factorial research designs. This can be achieved by comparing the effects of prenatal immune challenge at distinct gestational stages, relative to prenatal control treatment, on the susceptibility to structural and functional brain abnormalities in postnatal life. Such an experimental approach has been successfully used to study the influence of the precise timing on brain and behavioral abnormalities induced by prenatal exposure to a virallike acute phase response in mice (Meyer et al., 2006a,b, 2008c). As reviewed in more detail elsewhere (Meyer et al., 2007, in press-a), prenatal PolyI:C-induced immune challenge in early/middle gestation (gestation day 9 in the mouse species) leads to a pathological profile characterized by suppression in exploratory behavior, abnormalities in selective associative learning in the form of latent inhibition disruption and loss of the US-preexposure effect, impairments in sensorimotor gating in the form of reduced prepulse inhibition, enhanced sensitivity to the indirect dopamine-receptor agonist amphetamine and (to a lesser extent) the non-competitive NMDA-receptor antagonist dizocilpine (MK801), as well as deficiency in spatial working memory when the demand on temporal retention is high (Table 2). On the other hand, prenatal immune challenge in late gestation (gestation day 17 in the mouse species) leads to a partially overlapping symptom profile involving the emergence of perseverative behavior in the

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form of retarded reversal learning, spatial working memory impairments even when the demand on temporal retention is low, potentiated response to acute amphetamine and dizocilpine (MK-801) challenge, and loss of the US-pre-exposure effect (Table 2). Hence, experimental findings from the prenatal PolyI:C model in mice suggest that prenatal exposure to a viral-like acute phase response in both early/middle and late pregnancy is efficacious in causing functional brain abnormalities (Meyer et al., 2006a,b, 2007, 2008c). Importantly, this experimental model indicates that prenatal immune challenge in early/middle gestation (gestation day 9) may exert a more extensive impact on behavioral symptom profiles relevant to schizophrenia in comparison with infection occurring in late gestation (gestation day 17). Early/middle pregnancy (gestation day 9) and late pregnancy (gestation day 17) in the mouse roughly correspond to the middle/end of the first trimester and to the middle of the second trimester of human pregnancy, respectively, with respect to developmental biology and percentage of gestation from mice to human (see Section 5.2). Hence, the experimental data obtained in the prenatal PolyI:C model in mice support the hypothesis that the first rather than the second trimester of human pregnancy may be the time window with maximal vulnerability to prenatal infection-induced risk of schizophrenia-like disorder (Brown et al., 2001, 2004a; Babulas et al., 2006; Sørensen et al., 2009). It is important to emphasize that from the findings obtained in the prenatal PolyI:C model in mice, we cannot generally conclude that all infectious and/or immune activating agents may exert a more extensive impact on the offspring’s postnatal brain functions when the maternal infectious exposure takes place in early

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compared to late gestational stages. In fact, possible interactions between immune stimulus specificity and fetal developmental windows may critically shape the vulnerability to infectioninduced disturbances in brain and behavioral development (Fortier et al., 2007; Fatemi et al., 2008a,b). In-vivo rodent models of prenatal immune challenge are excellent experimental tools to test this hypothesis directly by comparing the influence of the prenatal timing in distinct models, which are based on different infectious and/or immune activating agents. The dissociable functional consequences of prenatal immune challenge at distinct times of pregnancy further indicate that the precise times of maternal immune activation can differentially affect the development of the relevant neural substrates involved. This expectation has also been confirmed by recent investigations in experimental mouse models using the viral mimic PolyI:C (Meyer et al., 2006b, 2008a) or human influenza virus (Fatemi et al., 2008a,b). As recently reviewed elsewhere (Meyer et al., 2007, in press-a), infection-induced interference with brain development during distinct stages of fetal development can precipitate dissociable neuropathological symptom clusters in adult life. Fig. 4 depicts two examples of differential neuropathological consequences of prenatal PolyI:C-induced immune challenge in early/ middle and late gestation in mice. In addition to the neuropathological dissociations, maternal immune challenge at distinct times of pregnancy can also lead to a dissociating pattern of gene expression abnormalities in the offspring’s brain. This has been recently confirmed in the influenza infection model in mice (Fatemi et al., 2005, 2008a,b). Taken together, prenatal immune activation in rodents leads, at least in part, to differential brain and behavioral pathological

Fig. 4. Emergence of differential adult neuropathology following prenatal immune challenge by the viral mimic PolyI:C in early/middle and late gestation in mice. (A) Adult offspring of mothers treated with PolyI:C (5 mg/kg, i.v.) on gestation day 9 (GD9) display a noticeable reduction in prefrontal cortical dopamine D1 receptors compared the adult control (CON) offspring and offspring of mothers exposed to identical PolyI:C treatment on gestation day 17 (GD17). The photomicrographs show coronal brain sections at the level of the medial prefrontal cortex of representative CON, GD9 and GD17 offspring. The sections are stained for dopamine D1 receptors using standard immunohistochemical methods. Strongest staining intensities are shown in white/yellow, while the background is represented in dark purple (bar inset). The relative optical densities are means  SEM; **P < 0.01, based on Mann–Whitney comparison between CON and GD9 offspring, and between GD9 and GD17 offspring. Scale bar = 200 mm. N(CON) = 8 [4<, 4,], N(GD9) = 8 [4<, 4,], N(GD17) = 8 [4<, 4,]. (B) Adult offspring of mothers treated with PolyI:C (5 mg/kg, i.v.) on GD17 but not on GD9 display a significant decrease in hippocampal expression of the NMDA-receptor subunit NR1 compared to adult CON offspring. The photomicrographs show coronal brain sections at the level of the dorsal hippocampus of representative CON, GD9 and GD17 offspring. The sections are stained for NMDA-receptor subunit NR1 using standard immunohistochemical methods. Strongest staining intensities are shown in white/yellow, while the background is represented in dark purple (bar inset). The relative optical densities are means  SEM; *P < 0.05, based on Mann–Whitney comparison between CON and GD17 offspring. Scale bar = 200 mm. N(CON) = 8 [4<, 4,], N(GD9) = 8 [4<, 4,], N(GD17) = 8 [4<, 4,]. All data are adapted from Meyer et al. (2008c).

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outcomes depending on the precise prenatal timing. This offers the opportunity to link specific neuronal dysfunctions with distinct forms of abnormal behavior, thus enabling the identification of intricate brain and behavioral relationships implicated in neurodevelopmental brain disorders with prenatal infectious etiologies. Further examination of in-utero immune challenge at distinct times of gestation may thus provide important new insight into the neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders with a neurodevelopmental component, including schizophrenia and autism. 5.2. Methodological considerations There are several methodological considerations that need to be taken into account in the design and interpretation of experimental studies aiming to explore the impact of the precise timing in rodent models of prenatal immune activation. The most critical issue is concerned with the extrapolation of the timing of brain development from experimental rodent species to humans. Prenatal development differs essentially between rodents and humans. More specifically, in terms of percentage of gestation and developmental biology, the gestational period in rats and mice would only cover the first and second trimester of human pregnancy (Clancy et al., 2001, 2007a,b; Kaufman, 2003). In rats and mice, the corresponding third trimester of human pregnancy would already be ex-utero, that is, during the first week of postnatal development. One consequence is that in-vivo rodent models can only translate into experimental investigations of the long-term brain and behavioral effects of prenatal immune challenge during the first and second trimester of human pregnancy. Early neonatal immune activation would thus be needed in experimental rodent models in order explore the longterm neurodevelopmental impact of immunological insults corresponding to late (third trimester) gestational infections in human (Hornig et al., 1999; Hornig and Lipkin, 2001; Pletnikov et al., 2000, 2002a,b,c; Nawa and Takei, 2006; Bonthius and Perlman, 2007; Sotoyama et al., 2007; Tohmi et al., 2007). The exact correspondence of fetal developmental progression can also significantly differ between two closely related species such as rats and mice. Indeed, many key events in fetal development occur approximately 2 days later in rats as compared to mice (Bayer et al., 1995; Clancy et al., 2001, 2007a,b; Kaufman, 2003). A careful examination of the spatiotemporal events in prenatal brain development across different species is therefore indispensable for the delineation of the precise neurodevelopmental impact of in-utero infections in humans as well as in rodents. The correspondence of fetal developmental progression in different species can be compared using database-driven websites. Such programs are based on statistical algorithms that integrate hundreds of empirically derived developing neural events in ten mammalian species, including rats, mice and humans (http://translatingtime.net/; see also Clancy et al., 2007b). 6. Studying gene–environment interactions Maternal infection during pregnancy is relatively common (Le et al., 2004; Laibl and Sheffield, 2005; Longman and Johnson, 2007). Yet, most offspring of mothers exposed to infection during pregnancy do not develop severe neurodevelopmental brain disorders such as schizophrenia or autism (Fatemi, 2005). This suggests that if in-utero exposure to infection plays a role in the etiology of these brain disorders, then it probably does so by interacting with other factors, including genetic factors. Therefore, exploring the influence of the genetic background seems highly

relevant in the association between prenatal immune challenge and risk of neurodevelopmental disorders. The combination of prenatal immune activation models with genetic animal models of neurodevelopmental disorders may represent a fruitful approach to identify critical interactions between genetic and infection-associated environmental factors, and to evaluate their modulatory influence on the vulnerability for specific forms of brain and behavioral disturbances. Notably, most of the current animal models of prenatal immune activation have been designed to mimic, in an accentuated fashion, the specific immunological events associated with an infection, leading to robust alterations in brain and behavior relevant to schizophrenia, autism and related disorders (Tables 2 and 3). However, these models can be modified in such a way that the maternal infectious manipulation is less severe and thus only leads to a restricted pathological phenotype in the offspring. One approach is to first evaluate the long-term neurobiobehavioral effects of prenatal exposure to immune activating agents across distinct doses (Shi et al., 2003; Meyer et al., 2005). This allows studying the impact of immune stimulus intensity in shaping the vulnerability to longlasting brain disorders, and it yields to the identification of threshold effects in neurodevelopmental brain dysfunctions associated with prenatal exposure to infection (Shi et al., 2003; Meyer et al., 2005). In a next step, the long-term brain and behavioral effects of prenatal immune challenge at low intensity may then be compared in animals with different genetic backgrounds. This can serve as a direct test of the hypothesis that genetically determined factors may modulate the vulnerability to infection-mediated abnormalities in brain and behavioral development. In the experimental study of such gene–environment interactions, one may first consider the examination of genes that are directly involved in innate and acquired immunity. Some of the identified genetic risk factors of schizophrenia and autism include promoter polymorphisms of pro-inflammatory (Boin et al., 2001; Zanardini et al., 2003) and anti-inflammatory cytokines (Chiavetto et al., 2002; Schosser et al., 2007), as well as human leukocyte antigens (HLA) and alleles (Wright et al., 2001; Boulanger and Shatz, 2004). The precise immune-related genetic background of the maternal host may influence the liability to certain infections, or result in an excessive or inappropriate inflammatory response in the maternal periphery and thereafter in the fetal system. This may in turn determine the impact of prenatal infection on early neurodevelopmental processes and subsequent brain and behavioral development. Experimental evidence for this hypothesis has recently been obtained in a mouse model of prenatal immune activation by the viral mimic PolyI:C. In a first study, Meyer et al. (2008a) have compared the neuropathological consequences of prenatal PolyI:C exposure in wild-type mice and transgenic mice constitutively overexpressing the anti-inflammatory cytokine IL-10 in macrophages. The results show that enhanced IL-10-mediated anti-inflammatory signaling during prenatal development is sufficient to prevent the emergence of multiple behavioral and pharmacological abnormalities in the adult offspring after prenatal immune challenge by PolyI:C (Meyer et al., 2008a). In another study, Smith et al. (2007) have demonstrated that prenatal PolyI:C treatment is inefficient in inducing behavioral mal-development in animals with a genetic deletion of the pro-inflammatory cytokine IL-6 relative to wild-type animals. Hence, recent investigations in mice designed to examine immunological gene–environment interactions have successfully shown that the association between prenatal immune challenge and emergence of schizophrenia-like behavioral and pharmacological dysfunctions is critically influenced by the anti-inflammatory and pro-inflammatory genetic background of the infected host. These initial findings should be

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extended to the evaluation of other immune-associated genetic risk factors of neurodevelopmental disorders (Boin et al., 2001; Wright et al., 2001; Zanardini et al., 2003; Boulanger and Shatz, 2004). Another model worth considering is the examination of genes that have been identified as major genetic susceptibility factors of neuropsychiatric disorders of neurodevelopmental origin. For schizophrenia, this may include neuregulin-1 (NRG-1), catecholO-methyltransferase (COMT), disrupted in schizophrenia-1 (DISC-1), and V-akt murine thymoma viral oncogene homolog 1 (AKT1) (Harrison and Weinberger, 2005); and for autism it may include methyl-CpG-binding protein-2 (Mecp2), ubiquitin protein ligase 3A (Ube3A), neuroligin (Nlgn), and serotonin transporter (SERT) (Maestrini et al., 2000; Bespalova and Buxbaum, 2003; Moy and Nadler, 2008). It is likely that many of these genes as such play only minor roles in infectious or inflammatory processes. Nevertheless, disruption of neurodevelopmental mechanisms by abnormal expression of these genes may act synergistically with prenatal infection/inflammation to increase the risk of long-lasting neurodevelopmental brain disorders. This scenario would be consistent with the hypothesis that the etiopathology of major neuropsychiatric disorders such as schizophrenia and autism involves aberrations in neurodevelopmental processes that are caused by an interaction between environmental and genetic factors (Tsuang et al., 2004; van Os et al., 2008). Therefore, the inclusion of genes beyond those involved in innate and acquired immunity is clearly warranted in experimental investigations of the role of gene–environment interactions in the association between prenatal infection and postnatal brain dysfunctions (Fatemi et al., 2005, 2008a,b).

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7.1. Preconceptional treatments Many severe immunological insults induced by viral infections can be effectively prevented by appropriate vaccinations (Wellington and Goa, 2003; Hoelscher et al., 2008). Therefore, one of the most effective strategies to reduce the incidence of infectionmediated neurodevelopmental brain disorders would be to prevent severe infections by maternal vaccination in the preconceptional period. Indeed, in the reported association between prenatal influenza infection and higher risk of schizophrenia, Brown et al. (2004a) estimate that 14–21% of schizophrenia cases would not have occurred if maternal infection had been prevented by influenza vaccinations. Likewise, appropriate vaccination may also significantly reduce the risk of schizophrenia associated with prenatal exposure to genital and reproductive infections (Babulas et al., 2006). In-vivo rodent models of prenatal immune challenge provide powerful experimental tools to evaluate the efficacy of preconceptional vaccination in the link between maternal immune challenge and risk of neurodevelopmental brain disturbances in the offspring. Indeed, they allow studying the effects of preconceptional vaccination (and corresponding non-treatment) within explicit comparison between distinct experimental groups of subjects, which can be prospectively identified as being predisposed to multiple brain and behavioral abnormalities by the prenatal maternal immunological manipulation. Against this background, the effectiveness of preconceptional vaccination in preventing prenatal infection-induced neurodevelopmental disorders can be tested within a relatively homogenous genetic population. 7.2. Acute interventions during pregnancy

7. Studying early interventions and preventive treatments In-vivo rodent models of prenatal immune activation provide a unique opportunity to establish and evaluate early interventions and preventive strategies in order to reduce the risk of brain disorders associated with in-utero exposure to infection and/or inflammation. There are at least three main strategies, which may prove to be efficient in preventing multiple brain abnormalities induced by prenatal immune challenge, namely interventions implemented (i) during the preconceptional period, (ii) during the acute phase of maternal exposure to infection, and (iii) during the early phases of the offspring’ postnatal development (Fig. 5).

Immediate interventions during the acute phase of the maternal infectious process may represent another efficient strategy for the prevention of neurodevelopmental brain abnormalities in the offspring. One promising approach would be to test whether acute anti-inflammatory treatment may be successful in limiting or halting the inflammatory processes in the maternal host and eventually in the fetal environment. This approach has been proven successful in recent experimental investigations in rodents, in which administration of the anti-inflammatory cytokine IL-10 to pregnant rodents given a uterine bacterial infection or LPS prevents fetal loss and white matter damage (Pang et al., 2005; Robertson et al., 2006, 2007). Similarly, maternal

Fig. 5. Possible strategies to prevent multiple brain and behavioral abnormalities induced by prenatal immune challenge. Maternal vaccination during the preconceptional period may be the first and most effective strategy to prevent the risk of neurodevelopmental brain disorders associated with prenatal exposure to infection. Immediate maternal interventions during the acute phases of gestational infection may represent another efficient strategy for the prevention of neurodevelopmental brain abnormalities in the offspring. These may be in the form of anti-inflammatory or antibiotic drug treatment. Early pharmacological and anti-inflammatory interventions during the offspring’s peri-adolescent development may be a third strategy to prevent the emergence of multiple brain and behavioral abnormalities. Finally, acute and/or chronic pharmacological treatments can be used to treat permanent brain dysfunctions symptomatically in adult life.

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administration of the anti-inflammatory drug N-acetylcysteine fully prevents the emergence of hippocampal dysfunctions and learning deficits in the offspring following prenatal maternal exposure to LPS (Lante´ et al., 2008). Together, these findings indicate that acute anti-inflammatory treatment during maternal infection and/or inflammation during pregnancy may indeed be a fruitful approach to prevent the development of infectionmediated brain disturbances in the offspring. However, it needs to be emphasized that a strong attenuation of pro-inflammatory and immune-stimulating signaling by antiinflammatory treatments may also facilitate rather than limit the infectious processes in the maternal host. For example, mycobacterial infection in mice with genetically enforced IL-10 overexpression results in higher bacterial loads and retarded bacterial clearance compared to wild-type mice (Lang et al., 2002). Similarly, high levels of IL-10 impair the host defense against pneumococcal pneumonia in mice (van der Poll et al., 1996). This illustrates that there may be adverse effects in dampening the inflammatory response to infection too much during pregnancy. Furthermore, compounds with anti-inflammatory properties may also have teratogenic effects (Ostensen and Ramsey-Goldman, 1998; Taylor and Low-Beer, 2001; Nahum et al., 2006), so that anti-inflammatory treatments in response to infectious exposures during pregnancy may induce additional deleterious effects on normal fetal development. Hence, a careful examination of the possible risks and benefits of maternal anti-inflammatory treatment during pregnancy is clearly warranted. This also applies to other acute interventions targeted at the pregnant maternal host, including viral vaccination (Mak et al., 2008) and administration of antibiotics (Nahum et al., 2006) during pregnancy. The advances in modeling maternal immune activation effects in rodents now provide a unique opportunity to systematically address these issues on an experimental basis, and to identify the possible risks and benefits of maternal anti-inflammatory, -viral and -bacterial interventions during pregnancy on long-term outcomes in the offspring. 7.3. Early preventive drug treatment in the offspring Therapeutic interventions during the offspring’ peri-adolescent development may represent a third major strategy to reduce the incidence of multiple brain dysfunctions following maternal infection during pregnancy. As already mentioned above, the full spectrum of behavioral, cognitive and pharmacological abnormalities induced by prenatal immune challenge in rats and mice are dependent on post-pubertal maturational processes and thus only emerge in adult but not pre-pubertal subjects (Zuckerman et al., 2003; Zuckerman and Weiner, 2003; Meyer et al., 2006c, 2008b; Ozawa et al., 2006). This progression of pathological symptoms from peri-adolescent to adult life is remarkably similar to the progression of psychotic symptoms in individuals prodromally symptomatic for schizophrenia. The (initial) prodromal phase of schizophrenia refers to a muted form of psychosis-related behavior, which precedes the onset of full-blown schizophrenic disorder (Klosterko¨tter et al., 2001). It has been suggested that early pharmacological treatment during the prodromal phase may prevent the subsequent emergence of a full-blown psychotic episode by attenuating or even halting the progression of the underlying pathology (McGlashan, 1996; Cornblatt et al., 2002). The underlying rationale is primarily based on the hypothesis that the longer a psychotic state is left untreated, the more severe the long-term psychopathological outcome is likely to be (Loebel et al., 1992; Haas et al., 1998; Perkins et al., 2005). For this reason, chronic administration of antipsychotic or antidepressant drugs to peri-adolescent and/or adolescent subjects with prodromal symptoms has recently been introduced as preventive treatment

of schizophrenia and other psychosis-related disorders in humans (Woods et al., 2003; McGlashan et al., 2003, 2006; Cornblatt et al., 2007). In spite of the laudable rationale of this preventive approach, its implementation has provoked several ethical concerns and therefore still remains highly controversial (Corcoran et al., 2005; Haroun et al., 2006). One relative unknown is the conversion rate amongst individuals with identified as being at high risk for full-blown psychosis. With an estimation as low as 30–50% (Yung et al., 2003), one immediate implication of such preventive practice is that a substantial number of false-positive subjects (who otherwise would not progress into full psychosis) would be exposed to unnecessary antipsychotic and/or antidepressant drug treatment (Block, 2006), while the long-term side effects of such exposure in these individuals are unknown. Hence, the relative benefits (i.e., successful prevention) and costs (i.e., long-term side effects in false-positive subjects) of preventive pharmacological interventions targeting peri-adolescent subjects, identified as being at high risk for schizophrenia in later life, must be comprehensively evaluated. Considering the apparent lack of knowledge about the longterm consequences of early preventive pharmacotherapy, along with the ethical concerns and technical difficulties to address these issues in humans, the explorative investigation of early preventive strategies in preclinical animal models is clearly warranted (Powell et al., 2003; Tenn et al., 2005). Since a defined experimental manipulation allows the clear segregation of high-risk subjects from controls, the efficiency of preventive pharmacotherapy can be studied without potential confounds arising from treatment in false-positive subjects. Prenatal immune activation models in rodents are highly suitable for the experimental investigation of preventive pharmacological intervention in schizophrenia and related psychotic disorders, because they mimic brain and behavioral abnormalities related to the full-blown schizophrenia phenotype in adult life (Tables 2 and 3); they incorporate etiological significance and the neurodevelopmental perspective of the disorder; and they capture the pathological progression from peri-adolescence to adulthood. This experimental approach has recently been used to study the efficacy of preventive antipsychotic or antidepressant drug treatment during the prodromal-like phase in the prenatal PolyI:C model of immune activation in mice (Meyer et al., in press-b). The experimental data show that peri-adolescent treatment with reference antipsychotic and antidepressant drugs can successfully block at least some of the psychosis-related behavioral and pharmacological abnormalities in subjects predisposed to adult brain pathology by exposure to prenatal immune challenge (Meyer et al., in press-b). At the same time, however, this initial study has revealed numerous negative influences of the early pharmacological intervention on normal behavioral development in control (i.e., ‘‘false-positive’’) subjects (Meyer et al., in press-b). Hence, prenatal immune activation models in rodents are sensitive for the detection of both beneficial and potentially harmful effects of chronic peri-adolescent pharmacological interventions designed for the preventive treatment of neuropsychiatric disorders, especially schizophrenia. 8. Concluding remarks Based on the epidemiological association between maternal infection during pregnancy and enhanced risk of neurodevelopmental brain disorders in the offspring, a number of in-vivo rodent models have since been established to study this link on an experimental basis. These models prove to be valid experimental strategies to test the hypothesis of causality and biological plausibility of human epidemiological findings, and to explore the

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Fig. 6. Summary of putative neuroimmunological, developmental and genetic factors (grey underlay) involved in the association between prenatal exposure to infection and enhanced risk of neurodevelopmental brain disorders. Both the precise timing of maternal infection and the genetic background of the maternal host determine the specificity of the maternal immune response to infection, which in turn may significantly influence the specificity of inflammation-mediated neurodevelopmental disturbances in the fetus. Genetic abnormalities may directly induce mal-neurodevelopment and/or act synergistically with prenatal infection/inflammation to increase the risk of long-lasting alterations in brain and behavioral development. Activation of the fetal immune system may also participate in the induction of altered neurodevelopmental trajectories; however, this is critically influenced by the precise stage of prenatal development. In addition to stimulation of immunological factors in the maternal immune system, some infectious pathogens may cross the placenta and negatively affect fetal brain development directly upon penetration into fetal brain tissue. Furthermore, activation of the maternal immune system induces direct physiological changes in the maternal host, including sickness behavior and stress, which in turn may result in (temporary) undernutrition of the mother. Together with the maternal and/or fetal inflammatory responses, these additional physiological changes may lead to fetal growth restriction, obstetric complications and alterations in post-partum maternal behavior, all of which may additionally affect normal fetal and/or neonatal brain development. Disturbances in early (prenatal and neonatal) brain development may predispose the offspring to alterations in subsequent postnatal brain maturation and may alter the offspring’s sensitivity to environmental factors during this period, finally cumulating into adult neuropathology and psychopathology. In-vivo models of prenatal infection and/or immune activation represent indispensable experimental tools to elucidate the relative contribution of these various neuroimmunological, developmental and genetic factors to enhanced risk of neurodevelopmental brain disorders following prenatal exposure to infection.

underlying neuroimmunological and developmental mechanisms, including possible interactions between immune-associated environmental and genetic factors (Fig. 6). Unique to the prenatal immune activation models is their holistic appreciation of intricate interactions amongst the immune system and the nervous system during early brain development (Fig. 6). They allow a multi-faceted, longitudinal monitoring of the disease process as it unfolds during the course of neurodevelopment from juvenile to adult stages of life, and the concomitant evaluation of the influence of external environmental factors (Fig. 6). This feature is particularly relevant for the neurodevelopmental perspective of schizophrenia and autism because the disorders’ pathophysiological and neuropathological mechanisms are assumed to be progressive in nature. In-vivo models

of prenatal immune activation are thus highly suitable for the elucidation of prenatal infectious contributions to progressive brain and behavioral abnormalities relevant to schizophrenia and autism. Finally, prenatal immune activation models offer a new avenue for the establishment and critical evaluation of distinct therapeutic interventions designed to reduce the risk of severe brain dysfunctions associated with in-utero exposure to infection and/or inflammation. Acknowledgements The studies performed at the authors’ institute were supported by the Swiss Federal Institute of Technology (ETH) Zurich (grant – 11 07/03; to UM and JF), the Swiss National Science Foundation (grant

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310000-118284/1; to UM and JF), and the National Institute of Child Health and Human Development (grant #1R01 HD046589-01A2; to SHF). JF received additional support from a 2009 NARSAD Distinguished Investigator Award. We are extremely grateful to Dr. Andrea Engler for running the cytokine assays (Fig. 3), and to Ste´phanie Vuillermot for providing the photographs (Fig. 1). References Abzug, M.J., Tyson, R.W., 2000. Picornavirus infection in early murine gestation: significance of maternal illness. Placenta 21, 840–846. Aleman, A., Kahn, R.S., Selten, J.P., 2003. Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch. Gen. Psychiatry 60, 565–571. Alexopoulou, L., Holt, A.C., Medzhitov, R., Flavell, R.A., 2001. Recognition of doublestranded RNA and activation of NF-kB by toll-like receptor 3. Nature 413, 732– 738. Allen, G., Courchesne, E., 2001. Attention function and dysfunction in autism. Front. Biosci. 6, D105–D119. Arguello, P.A., Gogos, J.A., 2006. 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