Elsevier

Behavioural Brain Research

Volume 204, Issue 2, 7 December 2009, Pages 322-334
Behavioural Brain Research

Research report
Neural basis of psychosis-related behaviour in the infection model of schizophrenia

https://doi.org/10.1016/j.bbr.2008.12.022Get rights and content

Abstract

Maternal infection during pregnancy is a notable risk factor for the offspring to develop severe neuropsychiatric disorders, including schizophrenia. One prevalent hypothesis suggests that infection-induced disruption of early prenatal brain development predisposes the organism for long-lasting structural and functional brain abnormalities, leading to the emergence of psychopathological behaviour in adulthood. The feasibility of this causal link has received considerable support from several experimental models established in both rats and mice. In this review, we provide an integrative summary of the long-term neuropathological consequences of prenatal exposure to infection and/or inflammation as identified in various experimental models of prenatal immune challenge. In addition, we highlight how abnormalities in distinct brain areas and neurotransmitter systems following prenatal immune activation may provide a neural basis for the emergence of specific forms of psychosis-related behaviour. Specifically, we suggest that prenatal infection-induced imbalances in the mesolimibic and mesocortical dopamine pathways may constitute critical neural mechanisms for disturbances in sensorimotor gating, abnormalities in selective associative learning and hypersensitivity to psychostimulant drugs. On the other hand, the emergence of working memory deficiency following prenatal immune challenge may be crucially linked to the concomitant disruption of GABAergic and glutamatergic functions in prefrontal cortical and hippocampal structures. Notably, many of the identified neuronal abnormalities are directly implicated in the neuropathology of schizophrenia. The findings from prenatal infection models of schizophrenia thus provide considerable experimental evidence for the assumption that prenatal exposure to infection and/or inflammation is a relevant environmental link to specific neuronal abnormalities underlying psychosis-related behaviour in humans.

Introduction

Schizophrenia is a major form of psychotic illness characterised by impaired thinking, emotions, and behaviour. Multiple lines of evidence suggest that this disabling brain disorder is of neurodevelopmental origin, in which the primary cerebral insult or pathological process occurs during early brain development long before the illness is clinically manifest [133], [149], [155], [184]. Together with a strong genetic contribution [78], various environmental factors appear to increase the risk of schizophrenia and other psychosis-related disorders [48], [111], [142]. Many of these factors operate at prenatal or early postnatal stages of life, that is, during the critical periods of early central nervous system (CNS) development.

Maternal infection during pregnancy is one of the environmental factors that significantly increases the risk of schizophrenia and related disorders in the offspring [25], [33], [34], [144]. This association does not appear to be limited to a single pathogen. Indeed, a multitude of infectious agents seems to be involved, including influenza [30], [105], [112], [166], rubella [31], toxoplasma gondii [32], [128], measles [173], polio [167], herpes simplex [35], and genital and/or reproductive infections [10]. One implication is that factors common to the immune response to a multitude of infectious agents may be the critical mediators of the association between prenatal infection and risk of schizophrenia. As extensively reviewed elsewhere [69], [116], [122], abnormal expression of pro-inflammatory cytokines and other mediators of inflammation in the maternal host and eventually in the foetal brain may interfere with normal foetal brain development [9], [117], [162]. This early inflammatory insult may predispose the offspring to long-lasting changes in subsequent brain and behavioural development and ultimately lead to adult neuropathology and associated psychosis-related behaviour in adolescence or early adulthood.

The feasibility of a causal link between maternal infection during pregnancy and higher risk of brain and behavioural pathology in the offspring has received considerable support from several experimental models established in both rats and mice. In these models, pregnant rats or mice are exposed to specific viral pathogens, immune-stimulating agents or pro-inflammatory cytokines, and the long-term brain and behavioural effects of the prenatal maternal manipulations are then evaluated in the offspring. A multitude of behavioural, cognitive and pharmacological abnormalities has been detected in adult mice and rats following prenatal exposure to human influenza virus [160], the viral mimic polyriboinosinic–polyribocytidilic acid (PolyI:C) [109], [114], [115], [116], [117], [118], [119], [120], [121], [122], [143], [160], [162], [191], [198], [199], [200], the bacterial endotoxin lipopolysaccharide (LPS) [26], [65], [66], [71], [153], [154], and the pro-inflammatory cytokine interleukin (IL)-6 [158], [162]. The spectrum of the functional deficits induced by the various prenatal immunological insults is summarised in Table 1.

The multiplicity of the adult behavioural, cognitive and pharmacological dysfunctions observed in prenatally immune challenged offspring suggests that the perturbations caused by the prenatal immunological manipulation are widespread, and fundamental to a range of normal neuropsychological functions. Importantly, many of the prenatal infection-induced behavioural, cognitive and pharmacological dysfunctions in adult rats and mice are implicated in some of the most critical phenotypes of schizophrenia and other psychosis-related disorders [7], [106], [115]. These include sensorimotor gating deficiency, abnormalities in selective associative learning, working memory impairment, enhanced sensitivity to psychostimulant drugs, and deficits in social behaviour (Table 1). The prenatal immune activation models thus enjoy a high level of face validity to schizophrenia-like psychopathology. The long-term effects of prenatal immune activation in rodents also mimic the characteristic maturational delay in disease onset of schizophrenia [133], [149], [155], [184], because the full spectrum of prenatal infection-induced behavioural, cognitive, and pharmacological abnormalities emerges only after the post-pubertal stage of development [119], [121], [143], [154], [198], [200]. Furthermore, some of the behavioural and cognitive deficits induced by in utero immune challenge in rats and mice can be normalized by acute and/or chronic antipsychotic drug treatment [160], [143], [153], [198], suggesting that the prenatal immune activation models are also valid models of schizophrenia-like dysfunctions with respect to predictive validity.

One plausible account of the neural bases underlying the emergence of a wide spectrum of behavioural, cognitive and pharmacological dysfunctions after prenatal immune activation may be that they are indicative of multiple structural brain abnormalities. In fact, given that the immunological insult takes place early in development, it can be expected that foetal brain inflammation induces wide-ranging neurodevelopmental sequelae, eventually leading to multiple neuroanatomical and neurochemical abnormalities in adult life. Direct support for this suggestion is yielded by numerous immunohistochemical, gene expression and neurochemical analyses in rats and mice, which demonstrate a wide spectrum of neuroanatomical and neurochemical changes in the adult CNS following prenatal exposure to infection and/or inflammation.

In this review, we provide an integrative summary of the long-term neuropathological consequences of prenatal exposure to infection and/or inflammation as identified in various experimental models of prenatal immune activation in rats and mice. In addition, we highlight how infection-induced abnormalities in distinct brain areas and/or neurotransmitter systems may provide a neural basis for specific forms of psychosis-related behaviour. Since the behavioural effects of prenatal immune activation reach their prominence in adulthood [119], [121], [143], [154], [198], [200], a special emphasis is placed on the brain and behavioural relationships at the adult stage of development.

Section snippets

The long-term neuropathological consequences of prenatal infection

Exposure to infection and/or inflammation during critical periods of prenatal life can be considered an “immunological lesion” of the developing brain, which is characterised by the presence of virulent pathogens in the foetal brain [8], [62], [187] and/or abnormal foetal expression of pro-inflammatory cytokines [9], [36], [71], [117], [118] and activated microglia [85], [137], [157]. This early lesion of the brain does not remain static, but rather, it is progressive in nature. That is, the

Linking specific neuronal dysfunctions with distinct forms of psychosis-related behaviour

Animal models are indispensable experimental tools in the study of possible causal links between specific neuronal dysfunctions and distinct forms of abnormal behaviour. They are therefore valuable in the exploration of specific brain and behavioural relationships in complex neuropsychiatric disorders such as schizophrenia, which is characterised by multiple behavioural, cognitive and pharmacological pathologies that are likely to involve neuronal disturbances beyond one single brain region and

Conclusions

Based on the human epidemiological association between maternal infection during pregnancy and higher risk of schizophrenia in the offspring [25], [33], [34], [144], an increasing number of experimental studies in rats and mice demonstrate that prenatal immune challenge is causally linked to the emergence of psychosis-related behaviour and pharmacological dysfunctions in adulthood. The infection-induced functional deficits are associated with multiple neuroanatomical, morphological and

Disclosure

The authors have no conflicts to disclose.

Acknowledgements

The studies performed at the authors’ institute were supported by the Swiss Federal Institute of Technology (ETH) Zurich, the Swiss National Science Foundation (SNSF). We are extremely grateful to Natalie Aeschbach-Jones for her editorial assistance.

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