A Longitudinal Examination of the Neurodevelopmental Impact of Prenatal Immune Activation in Mice Reveals Primary Defects in Dopaminergic Development Relevant to Schizophrenia

Abstract

Prenatal exposure to infection is a significant environmental risk factor in the development of schizophrenia and related disorders. Recent evidence indicates that disruption of functional and structural dopaminergic development may be at the core of the developmental neuropathology associated with psychosis-related abnormalities induced by prenatal exposure to infection. Using a mouse model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid, the present study critically evaluated this hypothesis by longitudinally monitoring the effects of maternal immune challenge during pregnancy on structural and functional dopaminergic development in the offspring from fetal to adult stages of life. Our study shows that prenatal immune challenge leads to dopaminergic maldevelopment starting as early as in the fetal stages of life and produces a set of postnatal dopaminergic abnormalities that is dependent on postnatal maturational processes. Furthermore, our longitudinal investigations reveal a striking developmental correspondence between the ontogeny of specific dopaminergic neuropathology and the postnatal onset of distinct forms of dopaminedependent functional abnormalities implicated in schizophrenia. Prenatal immune activation thus appears to be a significant environmental risk factor for primary defects in normal dopaminergic development and facilitates the expression of postnatal dopamine dysfunctions involved in the precipitation of psychosis-related behavior. Early interventions targeting the developing dopamine system may open new avenues for a successful attenuation or even prevention of psychotic disorders following neurodevelopmental disruption of dopamine functions.

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

“…Consistent with previous reports (Lipina et al, 2013;Vuillermot et al, 2010), we found that poly(I:C)--induced prenatal immune activation induced an adult onset of PPI deficits (Fig.1A). ANOVA yielded a significant main effect of age [F(1,28) = 136.75, p < 0.001], reflecting the general increase in % PPI displayed by adult relative to pubescent animals, as well as a significant interaction between age and prenatal treatment [F(1,28) = 4.80, p < 0.05].…”

“…The animals were killed on PND 40 and PND 90 to match the age of those offspring, which were assigned to the immunohistochemical evaluations of glial and synaptic markers. The pubescent and adult stages were defined based on the gradual attainment of sexual maturity and age--specific behavioral discontinuities from younger to older animals (Spear, 2000) and based on our previous findings revealing a post--pubertal onset of PPI deficits following poly(I:C)--induced prenatal immune activation in mice (Vuillermot et al, 2010). 9…”

“…The stimulus--onset asynchrony of the prepulse and pulse stimuli on all prepulse--plus--pulse trials was 100 ms (onset--to--onset). The protocol used for the PPI test was extensively validated before (e.g., Vuillermot et al, 2010). A session began with the animals being placed into the Plexiglas enclosure.…”

“…The dissected brains were postfixed in the same fixative for 6 h and processed for antigen retrieval involving overnight incubation in citric acid buffer (pH 4.5) followed by a 90 s microwave treatment at 480 W according to protocols established before Vuillermot et al, 2010). The brains were then cryoprotected using 30% sucrose in PBS, frozen with powdered dry ice, and stored at −80°C until further processing.…”

“…Disruption of normal fetal development (Meyer et al, 2008;Vuillermot et al, 2010), together with subsequent changes in brain maturation Piontkewitz et al, 2011;Richetto et al, 2014), may then confer increased risk of behavioral and cognitive dysfunctions in later life.…”