Urs Meyer

The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology.

Disturbance to early brain development is implicated in several neuropsychiatric disorders including autism, schizophrenia, and mental retardation. Epidemiological studies have indicated that the risk of developing these disorders is enhanced by prenatal maternal infection, presumably as a result of neurodevelopmental defects triggered by cytokine-related inflammatory events. Here, we demonstrate that the effects of maternal immune challenge between middle and late gestation periods in mice are dissociable in terms of fetal brain cytokine responses to maternal inflammation and the pathological consequences in brain and behavior. Specifically, the relative expression of pro- and anti-inflammatory cytokines in the fetal brains in response to maternal immune challenge may be an important determinant among other developmental factors for the precise pathological profile emerging in later life. Thus, the middle and late gestation periods correspond to two windows with differing vulnerability to adult behavioral dysfunction, brain neuropathology in early adolescence, and of the acute cytokine responses in the fetal brain.

Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs

The rate of formation of the three initial metabolites of cyclosporine metabolism has been determined in liver microsomes of 15 kidney transplant donors. Interindividual variation in metabolite formation was considerable but all three metabolites varied in parallel. An antiserum raised against a steroid‐inducible rat cytochrome P‐450 (P‐450 PCN) strongly inhibited the formation of these metabolites. Immunoquantitation of the protein recognized by a monoclonal antibody reacting with human cytochromes P‐450 of the P‐450III gene family, homologues of rat P‐450 PCN and rabbit P‐4503C, revealed a high degree of correlation with microsomal cyclosporine metabolism. The data suggest that this cytochrome P‐450 is the major cyclosporine‐metabolizing enzyme in human liver. The substrate specificity and the known inducers and inhibitors of this cytochrome P‐450 explain several clinically observed drug interactions with cyclosporine.

Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia

Epidemiological studies have indicated an association between maternal bacterial and viral infections during pregnancy and the higher incidence of schizophrenia in the resultant offspring post-puberty. One hypothesis asserts that the reported epidemiological link is mediated by prenatal activation of the foetal immune system in response to the elevation of maternal cytokine level due to infection. Here, we report that pregnant mouse dams receiving a single exposure to the cytokine-releasing agent, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 2.5, 5.0, or 10.0 mg/kg) on gestation day 9 produced offspring that subsequently exhibited multiple schizophrenia-related behavioural deficits in adulthood, in comparison to offspring from vehicle injected or non-injected control dams. The efficacy of the PolyI:C challenge to induce cytokine responses in naïve non-pregnant adult female mice and in foetal brain tissue when injected to pregnant mice were further ascertained in separate subjects: (i) a dose-dependent elevation of interleukin-10 was detected in the adult female mice at 1 and 6h post-injection, (ii) 12 h following prenatal PolyI:C challenge, the foetal levels of interleukin-1beta were elevated. The spectrum of abnormalities included impairments in exploratory behaviour, prepulse inhibition, latent inhibition, the US-pre-exposure effect, spatial working memory; and enhancement in the locomotor response to systemic amphetamine (2.5 mg/kg, i.p.) as well as in discrimination reversal learning. The neuropsychological parallels between prenatal PolyI:C treatment in mice and psychosis in humans, demonstrated here, leads us to conclude that prenatal PolyI:C treatment represents one of the most powerful environmental-developmental models of schizophrenia to date. The uniqueness of this model lies in its epidemiological and immunological relevance. It is, sui generis, ideally suited for the investigation of the neuropsychoimmunological mechanisms implicated in the developmental aetiology and disease processes of schizophrenia.

Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice.

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.

Epidemiology-driven neurodevelopmental animal models of schizophrenia

Human epidemiological studies have provided compelling evidence that the risk of developing schizophrenia is significantly enhanced following prenatal and/or perinatal exposure to various environmental insults, including maternal exposure to stress, infection and/or immune activation, nutritional deficiencies and obstetric complications. Based on these associations, a great deal of interest has been centered upon the establishment of neurodevelopmental animal models which are based on prenatal and/or perinatal exposure to such environmental stimuli. In the present review, we describe this relatively novel class of epidemiology-based animal models in relation to the etiology, neurobiology and psychopharmacology of schizophrenia. Thereby, we discuss the general design and practical implementation of these models, and we provide an integrative summary of experimental findings derived from diverse epidemiology-based models, including models of maternal exposure to psychological stress, glucocorticoid treatment, viral infection, immune activating agents, protein deprivation, vitamin D deficiency, as well as models of obstetric complications in the form of birth by Caesarian section and perinatal/postnatal hypoxia. We highlight that the long-term consequences of prenatal exposure to these environmental challenges in animals successfully capture a broad spectrum of structural and functional brain abnormalities implicated in schizophrenia, some of which can be normalized by acute and/or chronic antipsychotic drug treatment. We thus conclude that epidemiology-driven neurodevelopmental models of schizophrenia are characterized by a high level of face, construct and predictive validity, including intrinsic etiological significance to the disorder. They also fulfill the expectation of the neurodevelopmental theory, such that the effects of prenatal environmental insults often only emerge after puberty. Epidemiologically based animal models not only provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, but they also offer important new avenues for the elucidation of neurobiological, neuroendocrine and neuroimmunological mechanisms involved in the etiopathogenesis of schizophrenia and related disorders.

A Review of the Fetal Brain Cytokine Imbalance Hypothesis of Schizophrenia

Maternal infection during pregnancy increases the risk of schizophrenia and other brain disorders of neurodevelopmental origin in the offspring. A multitude of infectious agents seem to be involved in this association. Therefore, it has been proposed that factors common to the immune response to a wide variety of bacterial and viral pathogens may be the critical link between prenatal infection and postnatal brain and behavioral pathology. More specifically, it has been suggested that the maternal induction of pro-inflammatory cytokines may mediate the neurodevelopmental effects of maternal infections. Here, we review recent findings from in vitro and in vivo investigations supporting this hypothesis and further emphasize the influence of enhanced anti-inflammatory cytokine signaling on early brain development. Disruption of the fetal brain balance between pro- and anti-inflammatory cytokine signaling may thus represent a key mechanism involved in the precipitation of schizophrenia-related pathology following prenatal maternal infection and innate immune imbalances.

Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice.

Double Whammy Psychopathologies that cannot be explained by simple genetic or environmental circumstances may sometimes result from complex interplay between multiple inputs. Giovanoli et al. (p. 1095) analyzed the interactions between prenatal and postnatal stressors in mice to see what synergies give rise to psychopathologies in the adult mice. The results suggest that susceptibilities arise when mice are exposed to prenatal infection and also exposed to stressors around puberty. Stressors delivered later in adolescence did not seem to produce the same susceptibility. Although the mechanisms that impose the delay between stressors and psychopathology remain obscure, the timing and sequence of the triggers hint at possible cellular causes. Unfortunate synergies between stressors at vulnerable stages may underlie psychopathologies in mice. Prenatal infection and exposure to traumatizing experiences during peripuberty have each been associated with increased risk for neuropsychiatric disorders. Evidence is lacking for the cumulative impact of such prenatal and postnatal environmental challenges on brain functions and vulnerability to psychiatric disease. Here, we show in a translational mouse model that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. We further demonstrate that the prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress. Our findings reveal interactions between two adverse environmental factors that have individually been associated with neuropsychiatric disease and support theories that mental illnesses with delayed onsets involve multiple environmental hits.

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

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.

Schizophrenia and Autism: Both Shared and Disorder-Specific Pathogenesis Via Perinatal Inflammation?

Prenatal exposure to infection and subsequent inflammatory responses have been implicated in the etiology of schizophrenia and autism. In this review, we summarize current evidence from human and animal studies supporting the hypothesis that the pathogenesis of these two disorders is linked via exposure to inflammation at early stages of development. Moreover, we propose a hypothetical model in which inflammatory mechanisms may account for multiple shared and disorder-specific pathological characteristics of both entities. In essence, our model suggests that acute neuroinflammation during early fetal development may be relevant for the induction of psychopathological and neuropathological features shared by schizophrenia and autism, whereas postacute latent and persistent inflammation may contribute to schizophrenia- and autism-specific phenotypes, respectively.

The Neurodevelopmental Impact of Prenatal Infections at Different Times of Pregnancy: The Earlier the Worse?

Environmental insults taking place in early brain development may have long-lasting consequences for adult brain functioning. There is a large body of epidemiological data linking maternal infections during pregnancy to a higher incidence of psychiatric disorders with a presumed neurodevelopmental origin in the offspring, including schizophrenia and autism. Although specific gestational windows may be associated with a differing vulnerability to infection-mediated disturbances in normal brain development, it still remains debatable whether and/or why certain gestation periods may confer maximal risk for neurodevelopmental disturbances following the prenatal exposure to infectious events. In this review, the authors integrate both epidemiological and experimental findings supporting the hypothesis that infection-associated immunological events in early fetal life may have a stronger neurodevelopmental impact compared to late pregnancy infections. This is because infections in early gestation may not only interfere with fundamental neurodevelopmental events such as cell proliferation and differentiation, but it may also predispose the developing nervous system to additional failures in subsequent cell migration, target selection, and synapse maturation, eventually leading to multiple brain and behavioral abnormalities in the adult offspring. The temporal dependency of the epidemiological link between maternal infections during pregnancy and a higher risk for brain disorders in the offspring may thus be explained by specific spatiotemporal events in the course of fetal brain development. NEUROSCIENTIST 13(3):241—256, 2007.