In utero infection and adult schizophrenia

Brown, Alan S.; Süsser, Ezra

doi:10.1002/mrdd.10004

Cited by 230 publications

(136 citation statements)

References 43 publications

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“…Maternal infection during pregnancy increases the risk for several neuropsychiatric disorders in the offspring, including schizophrenia (Brown and Susser, 2002;Fatemi, 2005) and autism (Rodier and Hyman, 1998;Miller et al, 2005). Recent attempts to model this epidemiological link in animals has yielded considerable support for a causal relationship between in utero immune activation and the emergence of adult psychopathology.…”

Section: Introductionmentioning

confidence: 99%

Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge

Meyer

Nyffeler

Schwendener

et al. 2007

Neuropsychopharmacol

197

196

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Prenatal exposure to infections represents a risk factor for the emergence of neuropsychiatric disorders in later life, including schizophrenia and autism. However, it remains essentially unknown whether this association is primarily attributable to prenatal and/or postnatal maternal effects on the offspring. Here, we addressed this issue by dissecting the relative contributions of prenatal inflammatory events and postnatal maternal factors in an animal model of prenatal viral-like infection. Pregnant mice were exposed to the inflammatory agent polyriboinosinic-polyribocytidilic acid (PolyI:C; 5 mg/kg, i.v.) or vehicle treatment on gestation day 9, and offspring born to PolyI:Cand vehicle-treated dams were cross fostered to surrogate rearing mothers that had either experienced inflammatory or sham treatment during pregnancy. We demonstrate that a variety of dopamine-and glutamate-related pharmacological and neuroanatomical disturbances emerge after prenatal immune challenge regardless of whether neonates were raised by vehicle-or PolyI:C-exposed surrogate mothers. However, the adoption of prenatal control animals to immune-challenged surrogate mothers was also sufficient to induce specific pharmacological and neuroanatomical abnormalities in the fostered offspring. Multiple schizophrenia-related dysfunctions emerging after prenatal immune challenge are thus mediated by prenatal but not postnatal maternal effects on the offspring, but immunological stress during pregnancy may affect postpartum maternal factors in such a way that being reared by an immune-challenged surrogate mother can confer risk for distinct forms of psychopathology in adult life.

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Section: Introductionmentioning

confidence: 99%

Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge

Meyer

Nyffeler

Schwendener

et al. 2007

Neuropsychopharmacol

197

196

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“…3 Epidemiological studies have indicated that maternal infections during pregnancy increase the risk for these disorders in the offspring. [4][5][6][7] According to one hypothesis, the maternal cytokine response to infections may play a crucial role in this association, 8 because the induction of cytokines is a fundamental immunological event triggered by virtually any infection. 9 More specifically, it has been suggested that activation of pro-inflammatory cytokines, including interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNF)-a, mediate the neurodevelopmental effects of maternal infections on the offspring.…”

Section: Introductionmentioning

confidence: 99%

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

et al. 2007

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Maternal infections during pregnancy increase the risk for schizophrenia and related disorders of putative neurodevelopmental origin in the offspring. This association has been attributed to enhanced expression of pro-inflammatory cytokines in the fetal environment in response to maternal immunological stimulation. In contrast, the specific roles of anti-inflammatory cytokines are virtually unknown in this context. Here, we demonstrate that genetically enforced expression of the anti-inflammatory cytokine interleukin (IL)-10 by macrophages attenuates the long-term behavioral and pharmacological consequences of prenatal immune activation in a mouse model of prenatal viral-like infection by polyriboinosinic-polyribocytidilic acid (PolyI:C; 2 mg/kg, intravenously). In the absence of a discrete prenatal inflammatory stimulus, however, enhanced levels of IL-10 at the maternal-fetal interface by itself also precipitates specific behavioral abnormalities in the grown offspring. This highlights that in addition to the disruptive effects of excess pro-inflammatory molecules, a shift toward enhanced antiinflammatory signaling in prenatal life can similarly affect cognitive and behavioral development. Hence, shifts of the balance between pro-and anti-inflammatory cytokine classes may be a critical determinant of the final impact on neurodevelopment following early life infection or innate immune imbalances.

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“…Maternal exposure, during pregnancy, to influenza (Brown et al, 2004a;Mednick et al, 1988), poliovirus (Suvisaari et al, 1999), rubella, measles, varicella-zoster (Brown and Susser, 2002), retrovirus (Yolken et al, 2000), and bacterial agents (O'Callaghan et al, 1994), has been associated with an increased risk for schizophrenia in the offspring. This suggests that a maternal immune response, common to various infectious agents, could influence fetal brain development and, consequently, lead to schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Neurobehavioral and Immunological Consequences of Prenatal Immune Activation in Rats. Influence of Antipsychotics

Romero

Ali

Molina‐Holgado

et al. 2006

Neuropsychopharmacol

128

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Increasing evidence suggests that pre-or perinatal events that influence the immune system contribute to the development of behavioral or neuropsychiatric disorders. For instance, exposure of pregnant rats to the bacterial endotoxin lipopolysaccharide (LPS) disrupts sensorimotor information processing, as assessed by the prepulse inhibition test (PPI), and also the immune function in adult offspring, which might be of particular relevance as regards schizophrenia. However, the consequences of maternal LPS exposure during pregnancy on synaptic functioning in adult offspring and, more importantly, the therapeutic opportunity to re-establish PPI and immune function have still to be demonstrated. In this work, we analyzed the consequences of prenatal LPS exposure on dopaminergic neurotransmission and presynaptic markers in adult brain areas related to PPI circuitry. In addition, we tested whether oral treatment with the typical antipsychotic drug haloperidol (HAL) could reinstate PPI performances and cytokine serum levels in six-month-old male rats with prenatal LPS exposure. Both sensory information processing deficits and immune anomalies induced by prenatal exposure to LPS were accompanied by changes in dopaminergic neurotransmission and synaptophysin expression. It is important to note that PPI disruption and serum increases in cytokines induced by prenatal LPS exposure were both reversed by HAL. Taken together, these results demonstrate the critical influence of prenatal immune events on the functioning of adult nervous and immune systems, in association with the putative role of the immune system in the development of behavior relevant to schizophrenia.

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In utero infection and adult schizophrenia

Cited by 230 publications

References 43 publications

Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge

Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

Neurobehavioral and Immunological Consequences of Prenatal Immune Activation in Rats. Influence of Antipsychotics

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