Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia

Abstract

Prenatal exposure to infection is associated with increased liability to schizophrenia, and it is believed that such an association is mediated by the maternal immune response, in particular, the proinflammatory cytokines released by the maternal immune system, which may disrupt fetal brain development. Impaired capacity to ignore irrelevant stimuli is one of the central deficits in schizophrenia, and is manifested, among others, in loss of latent inhibition (LI), a phenomenon whereby repeated inconsequential pre-exposure to a stimulus impairs its subsequent capacity to signal significant consequences. We tested the effects of prenatal immune activation induced by peripheral administration of the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I : C) to pregnant dams, on LI in juvenile and adult offspring. Consistent with the characteristic maturational delay of schizophrenia, prenatal immune activation did not affect LI in the juvenile offspring, but led to LI disruption in adulthood. Both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) reinstated LI in the adult offspring. In addition, prenatal immune activation led to a postpubertal emergence of increased sensitivity to the locomotorstimulating effects of amphetamine and increased in vitro striatal dopamine release, as well as to morphological alterations in the hippocampus and the entorhinal cortex in the adult offspring, consistent with the well-documented mesolimbic dopaminergic and temporolimbic pathology in schizophrenia. These results suggest that prenatal poly I : C administration may provide a neurodevelopmental model of schizophrenia that reproduces a putative inducing factor; mimics the temporal course as well as some central abnormalities of the disorder; and predicts responsiveness to antipsychotic drugs.

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

“…Hence, we confirm here that maternal PolyI:C exposure can lead to functional deficits in multiple neuropsychological domains in the grown offspring, [14][15][16][17][18][19] and further reveal that the macrophagespecific overexpression of IL-10 in the maternal host can prevent the expression of the behavioral and cognitive deficits induced by prenatal immune activation. In the absence of a discrete inflammatory stimulus, however, enforced IL-10 overexpression by itself is linked to specific behavioral abnormalities in the form of deficient spatial exploration and associative learning.…”

“…Here, we focused on adult spatial exploration, sensorimotor gating and selective associative learning, because previous reports in rodents have repeatedly demonstrated that prenatal PolyI:C exposure leads to functional abnormalities in these neuropsychological domains when the animals reach adult age. [14][15][16][17][18][19] First, spatial exploration was studied in an open field by focusing on the time the animals spent in the central area of the field during a 30-min test period. This test is widely applied to assess explorative behavior in rodents.…”

“…12 They may also be critically involved in the precipitation of the long-term behavioral, cognitive and pharmacological consequences of prenatal immune challenge as shown in vivo. [13][14][15][16][17][18][19][20] In contrast, very little is known about the putative roles of anti-inflammatory cytokines in the association between prenatal inflammation and the emergence of brain and behavioral abnormalities. One of the best characterized anti-inflammatory cytokine is IL-10.…”

“…26,27 Maternal immune activation by PolyI:C exposure in rodents is known to precipitate a wide spectrum of behavioral, cognitive and pharmacological abnormalities in the adult offspring. [14][15][16][17][18][19] Hence, the combination of the prenatal PolyI:C model with a mouse model of genetically driven IL-10 overexpression by macrophages allows us to explore the effects of pro-and anti-inflammatory cytokine signaling on brain and behavioral development following prenatal inflammatory conditions and innate immune imbalances. Here, we focused on the impact of the genetically and environmentally induced immunological manipulations on behavioral functions and pharmacological responses known to be disrupted by prenatal immune challenge, including sensorimotor gating, selective associative learning, spontaneous exploratory behavior and sensitivity to the psychomotor-stimulant effects of dopaminergic and glutamatergic drug challenge.…”

“…Here, we focused on the impact of the genetically and environmentally induced immunological manipulations on behavioral functions and pharmacological responses known to be disrupted by prenatal immune challenge, including sensorimotor gating, selective associative learning, spontaneous exploratory behavior and sensitivity to the psychomotor-stimulant effects of dopaminergic and glutamatergic drug challenge. [14][15][16][17][18][19] …”