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

https://doi.org/10.1016/j.neubiorev.2009.05.001Get rights and content

Abstract

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, viral-like 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.

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, Brown, 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, Brown et al., 2004b, Brown et al., 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 schizophrenia- and 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 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 (Table 1, Table 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 psychosis-related 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), γ-aminobutyric 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.

Section snippets

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.

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, viral- or bacterial-like immune activating agents, or individual pro-inflammatory cytokines (Fig. 2). Different infectious and/or immune activating agents induce distinct but partly overlapping immune responses in the periphery, and they may exert

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

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 disorders 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

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.

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)

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 underlying neuroimmunological and developmental mechanisms,

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 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 (

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