Late Prenatal Immune Activation in Mice Leads to Behavioral and Neurochemical Abnormalities Relevant to the Negative Symptoms of Schizophrenia

Abstract

Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. We found that prenatal exposure to the viral mimic polyriboinosinic-polyribocytidilic acid (Poly-I:C; 5 mg/kg, i.v.) on gestation day (GD) 17 led to significant deficits in social interaction, anhedonic behavior, and alterations in the locomotor and stereotyped behavioral responses to acute apomorphine (APO) treatment in both male and female offspring. In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ-aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

“…However, Bitanihirwe et al (2010) found that male offspring of poly(I:C) (GD17) mouse dams exhibited abnormally enhanced LI in associative learning compared to prenatal salinetreated males (Bitanihirwe et al, 2010). Poly(I:C) female offspring did not differ from control female offspring.…”

“…Cytoarchitectural changes can also be seen in the adult animals exposed to immunogen as neonates such as enlargement of bilateral ventricles and alterations in axonal and dendritic arborization in the parietal cortex and substantia nigra (Fan et al, 2011). Common functional deficits seen in rodent offspring exposed to prenatal or neonatal immune activation include cognitive and social dysfunctions (Bilbo et al, 2005;Bitanihirwe et al, 2010;Ibi et al, 2009;Wang et al, 2010).…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…MIA in rats and mice causes dysfunction of GABAergic circuitry in the hippocampus, amygdala, and cortex (Canetta and Brown, 2012;Meyer, 2014). GABA content decreases (Bitanihirwe et al, 2010), GAD1 gene expression decreases (Deslauriers et al, 2013;Richetto et al, 2013), and GABA receptor subunit expression increases (Nyffeler et al, 2006) following immune activation during prenatal development. These effects appear to affect specifically PV þ interneurons (Ducharme et al, 2012;Ibi et al, 2010;Piontkewitz et al, 2012), although effects on other interneuronal cell types cannot be excluded.…”

Prenatal Immune Activation Interacts with GeneticNurr1Deficiency in the Development of Attentional Impairments

“…Organisms that tend to show impaired attentional shifting are expected to express the LI effect under parametric conditions that are insufficient for control animals to display LI (Weiner, 2003). Such attentional abnormalities are manifest in adult mice following prenatal treatment with a high dose of poly(I:C) (Bitanihirwe et al, 2010b), indicating that prenatal immune activation at high intensity is capable of inducing deficits in this cognitive domain. Here, we were interested to explore whether the combination of Nurr1 deficiency and mild prenatal immune activation may interact with each other to produce such attentional abnormalities, and therefore, we used parametric conditions with low amount of stimulus preexposure to facilitate the identification of potential LI persistence in Nurr1 ϩ/Ϫ offspring with additional prenatal poly(I:C) exposure.…”

“…Organisms that tend to show impaired attentional shifting are expected to express the LI effect under parametric conditions that are insufficient for control animals to display LI (Weiner, 2003). Such attentional abnormalities are manifest in adult mice following prenatal treatment with a high dose of poly(I:C) (Bitanihirwe et al, 2010b), indicating that prenatal immune activation at high intensity is capable of inducing deficits in this cognitive domain. Here, we show that mild prenatal immune challenge can synergistically interact with a genetic predisposition factor in the development of LI persistence: Whereas poly(I: C)-treated Nurr1 ϩ/Ϫ offspring displayed a marked LI effect (indexed by reduced conditioned freezing in PE subjects compared with NPE subjects), all other groups showed no similar LI effect during the critical tone-CS test phase of the LI paradigm (Fig.…”