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

Abstract

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.

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

“…Such abnormalities have indeed been noted by numerous previous investigations using prenatal poly(I:C) models in rodents (Dickerson et al, 2010(Dickerson et al, , 2014Savanthrapadian et al, 2013;Wolff and Bilkey, 2015;Zhang and van Praag, 2015). Furthermore, the synaptic deficits may also contribute to the cognitive impairments that have frequently been observed following prenatal immune activation (reviewed in Boksa, 2010;Harvey and Boksa, 2012;Reisinger et al, 2015).…”

“…Given the validity of the prenatal poly(I:C) administration model for neuropsychiatric disorders with neurodevelopmental components Meyer, 2014;Reisinger et al, 2015), our findings suggest that prenatal infection and/or inflammation may be an early environmental risk factor for the development of synaptic abnormalities in these disorders.…”

“…Against these backgrounds, the present study aimed at exploring potential associations between impaired synaptic development and microglial abnormalities in a model of prenatal immune activation with relevance to neurodevelopmental disorders. We 5 used a well--established mouse model of maternal treatment with the viral mimetic polyriboinosinic--polyribocytidilic acid [poly(I:C)], which is known to capture a wide spectrum of neuronal and behavioural abnormalities relevant to psychiatric disorders, especially schizophrenia and autism (reviewed in Meyer, 2014;Reisinger et al, 2015).…”

“…To confirm the negative influence of prenatal immune challenge on behavior, we measured sensorimotor gating using the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex. PPI deficiency is a well--replicated behavioral manifestation emerging in rats and mice exposed to prenatal immune activation (for a review, see Boksa, 2010;Meyer, 2014;Reisinger et al, 2015) and is frequently observed in neuropsychiatric disorders with neurodevelopmental components (Braff et al, 2001;Swerdlow et al, 2008). All analyses were conducted during puberty and adulthood in order to identify possible maturation--dependent effects of prenatal immune activation.…”

Consequences of gestational diabetes to the brain and behavior of the offspring

“…Manipulation of maternal immune system appears to be a common denominator important for determination of later outcomes (Estes and MacAllister 2016). In fact, a broader range of environmental distresses during the prenatal period have been associated to the development of schizophrenia and autism later in life (Reisinger et al 2015). Clinical evidence suggest that the offspring of GD mothers have increased risk of developing schizophrenia (Van Lieshout andVoruganti 2008, Boksa 2004) and autism (Gardener et al 2009, Xiang et al 2015 during adolescence and adulthood.…”