Research reportNeural basis of psychosis-related behaviour in the infection model of schizophrenia
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.
References (200)
Alterations of serotonin transmission in schizophrenia
Int Rev Neurobiol
(2007)- et al.
Theories of basal forebrain organization and the “emotional motor system”
Prog Brain Res
(1996) - et al.
Modeling madness in mice: one piece at a time
Neuron
(2006) - et al.
Hippocampal modulation of sensorimotor processes
Prog Neurobiol
(2003) - et al.
Hyperactivity and disruption of prepulse inhibition induced by N-methyl-d-aspartate stimulation of the ventral hippocampus and the effects of pretreatment with haloperidol and clozapine
Neuroscience
(2001) - et al.
Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics
Schizophr Res
(1997) - et al.
Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects
Neuroscience
(1996) Cytokine actions in the central nervous system
Cytokine Growth Factor Rev
(1998)- et al.
Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia
Neuropsychopharmacology
(2002) - et al.
Dissociative effects of apomorphine infusions into the medial prefrontal cortex of rats on latent inhibition, prepulse inhibition and amphetamine-induced locomotion
Neuroscience
(1999)