Hypolocomotive behaviour associated with increased microglia in a prenatal immune activation model with relevance to schizophrenia

Eynde, Karlien Van den; Missault, Stephan; Fransén, Erik; Raeymaekers, L.; Willems, Roland; Drinkenburg, Wilhelmus; Timmermans, Jean‐Pierre; Kumar‐Singh, Samir

doi:10.1016/j.bbr.2013.10.005

Cited by 90 publications

(76 citation statements)

References 51 publications

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“…Hence, even though abnormalities in microglia functions can occur following prenatal immune challenge (Borrell et al, 2002;Juckel et al, 2011;Van den Eynde et al, 2014;Zhu et al, 2014), our findings suggest that such changes are not a prerequisite for synaptic deficits to occur, at least within the dorsal and ventral hippocampus. This interpretation is consistent with the findings derived from disease models of chronic neurodegeneration, suggesting that microglia do not play an active role in either synaptic stripping or synapse degeneration in the hippocampal formation (Perry and O'Connor, 2010;Sisková et al, 2009).…”

mentioning

confidence: 68%

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

126

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Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre-and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1 levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation. AbstractPrenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre--and postsynaptic deficits.Using a well--established mouse model of maternal exposure to the viral mimetic polyriboinosinic--polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)--exposed and control mothers. We found that prenatal immune activation induced adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early--life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial a...

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mentioning

confidence: 68%

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

126

View full text Add to dashboard Cite

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“…However, other studies including both males and females show PPI deficits following poly-I:C in rats and mice of both sexes (Ratnayake et al 2014;Van den Eynde et al 2014;Zhu et al 2014), with the study by Van den Eynde being particularly well powered (n = 14-29/group), and one study found female specific deficits in PPI following poly-I:C exposure in rats (8mg/kg i.p. GD 14) (Vorhees et al 2012).…”

Section: Prenatal Immune Challenged Modelmentioning

confidence: 94%

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

Hill

2016

Neuroscience & Biobehavioral Reviews

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“…Concerning gene × environment interactions as the biological interface for the long-established "nature versus nurture" etiological principle, the Poly(I:C) MIA model has contributed to the elucidation of some of the key players involved in the pathogenesis of schizophrenia (Ozawa et al, 2006;Dickerson & Bilkey, 2013;Van den Eynde et al, 2013). For example, following Poly(I:C)-assisted MIA, mice with mutations in the Disrupted in Schizophrenia 1 gene (DISC1) -originally identified in a case of familial human schizophrenia (Chubb et al, 2008;Jaaro-Peled et al, 2009) -display higher susceptibility to the development of behavioral features associated with schizophrenia (Lipina et al, 2013).…”

Section: Schizophrenia Dickerson and Bilkey 2013mentioning

confidence: 99%

The Poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery

Reisinger

Khan

Kong

et al. 2015

Pharmacology & Therapeutics

205

199

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Increasing epidemiological and experimental evidence implicates gestational infections as one important factor involved in the pathogenesis of several neuropsychiatric disorders. Corresponding preclinical model systems based upon maternal immune activation (MIA) by treatment of the pregnant female have been developed. These MIA animal model systems have been successfully used in basic and translational research approaches, contributing to the investigation of the underlying pathophysiological mechanisms at the molecular, cellular and behavioral levels. The present article focuses on the application of a specific MIA rodent paradigm, based upon treatment of the gestating dam with the viral mimic polyinosinic-polycytidilic acid (Poly(I:C)), a synthetic analog of double-stranded RNA (dsRNA) which activates the Toll-like receptor 3 (TLR3) pathway. Important advantages and constraints of this animal model will be discussed, specifically in light of gestational infection as one vulnerability factor contributing to the complex etiology of mood and psychotic disorders, which are likely the result of intricate multi-level gene×environment interactions. Improving our currently incomplete understanding of the molecular pathomechanistic principles underlying these disorders is a prerequisite for the development of alternative therapeutic approaches which are critically needed in light of the important drawbacks and limitations of currently available pharmacological treatment options regarding efficacy and side effects. The particular relevance of the Poly(I:C) MIA model for the discovery of novel drug targets for symptomatic and preventive therapeutic strategies in mood and psychotic disorders is highlighted in this review article.

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Hypolocomotive behaviour associated with increased microglia in a prenatal immune activation model with relevance to schizophrenia

Cited by 90 publications

References 51 publications

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

The Poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery

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