Research reportEffects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy
Introduction
It is generally accepted that schizophrenia is a disorder of neurodevelopmental origin [31], caused by both genetic and environmental factors [57]. Among environmental risk factors, an increased incidence of schizophrenia has been documented following prenatal infections with viruses such as influenza, measles, rubella, varicella-zoster and polio [10], [11], [40], [54], [56], and with the protozoa causing toxoplasmosis [12]. Increased risk for schizophrenia has also been associated with maternal pneumonia during pregnancy [45], which is most commonly bacterial in origin [25]. The wide variety of infectious agents associated with increased risk for schizophrenia suggests that mechanisms common to various prenatal infections may affect fetal development.
To model maternal infection during pregnancy, live viruses as well as molecular immunogens like the bacterial endotoxin, lipopolysaccharide (LPS), or the viral mimic polyinosinic: polycytidylic acid (poly I:C) have been administered to pregnant rodents. Following gestational immune activation, changes relevant to the pathophysiology of schizophrenia have been observed in the offspring, including deficits in prepulse inhibition of acoustic startle (PPI) [41], [46], latent inhibition [62], object recognition [46], social interaction [51], increases in amphetamine-induced locomotion [19], [61], other alterations in dopaminergic function [4], [32], and hippocampal abnormalities [24]. However, there is a high degree of variability among these studies with respect to the nature of the immune challenge used and the gestational stage at which it is administered.
We and others [2], [7], [42], [46] have suggested that the deleterious consequences of maternal infection on fetal neurodevelopment may be mediated via circulating cytokines induced by the immunogens, rather than the immune agent acting directly on the fetuses. Intramuscular (im) turpentine injection, a well-documented model of local inflammation [16], [30], may be used to investigate this question, since unlike LPS and poly I:C, it does not enter the systemic circulation. Though these three immune models (LPS, poly I:C, turpentine) all induce sickness behaviors and febrile responses through circulating cytokines [15], [20], [37], the exact timing and quantity of cytokine released vary for each immunogen. Hence, their effect on fetal neurodevelopment may not be equivalent. We were therefore interested to compare the effects of these three different maternal immune treatments on offspring behavior.
Among behavioral outcomes investigated after prenatal immune treatment, PPI is particularly relevant to schizophrenia as it reveals deficits in sensory information gating believed to be an important feature of the illness. PPI is a well-established sensorimotor gating paradigm defined as “a profound decrease in startle magnitude when the startling pulse is preceded by a weak prepulse” [55]. PPI deficits in schizophrenic patients are well documented [9], [28], [34]. In mice, administration of influenza virus or poly I:C on embryonic day (E)9.5 or poly I:C on E12–17 decreases PPI in offspring [46], [51]. Similarly, in rats, administration of LPS on alternate days throughout the entire pregnancy leads to a marked PPI disruption [8]. However, no study has compared the effects of maternal immune treatment at different gestational periods on PPI. A recent study by Meyer et al. [43] indicated that maternal infection affected offspring explorative and perseverative behavior differentially depending on the gestational stage at which the immune agent was administered. This supports the idea that a window of vulnerability to infection during gestation may also exist for the production of other behavioral deficits, such as PPI disruption.
Thus, our aim was to compare the effects of maternal infection induced by physiological doses of different immune agents administered at different periods during gestation on PPI in the adult offspring. In order to do so, we administered pyrogenic doses of LPS, poly I:C, or turpentine to pregnant rats at one of three time points during gestation: E10–11, E15–16, and E18–19. These time points are representative of what has been used in animal models of maternal infection, and more importantly, coincide with different neurodevelopmental events, in particular with regard to the dopaminergic (DA) system [5], [47], known to be involved in the regulation of PPI [23] and possibly in the pathophysiology of schizophrenia [29].
Finally, to investigate whether the disruptive effects of LPS on PPI are strictly developmental, we also examined the effects of acute LPS administration on PPI in normal adult rats. A large body of literature indicates that LPS decreases performance in a number of cognitive tasks, including different types of conditioning [48], [52], and spatial learning [50]. This suggested that acute LPS could also disrupt the pre-cognitive processes involved in PPI.
Section snippets
Subjects and treatments
All procedures were performed in accordance with the guidelines established by the Canadian Council on Animal Care and were approved by the McGill University Animal Care Committee. For gestational LPS and poly I:C treatment, timed pregnant Sprague–Dawley rats (Charles River, Quebec, Canada) were injected intraperitoneally (ip) with LPS (from E. coli serotype 0111:B4, L-2630, Sigma, Canada) or poly I:C (Sigma, Canada) at the doses indicated, once daily, on two consecutive days, at one of the
Pregnancy outcome following gestational immune treatment
In order to model a physiological maternal infection, we aimed to administer to pregnant dams doses of the three immunogens which have been shown to produce optimal fever and cytokine induction in the rat, while having limited impact on maternal and pup survival (i.e. 50–100 μg/kg of LPS; 750–1000 μg/kg of poly I:C; 10 μl turpentine) [20], [36], [37]. Table 1 shows that, contrary to systemic administration of poly I:C and local inflammation by turpentine, systemic administration of LPS to pregnant
Discussion
In this study, we provide evidence that both systemic and local inflammation during specific gestational periods can alter PPI in the resulting adult offspring. Maternal infection with LPS on E15–16 or E18–19 significantly decreased PPI in adult male offspring, while LPS exposure on E10–11 had only marginal effects. Local inflammation by turpentine on E15, but not on E18 or E10, reduced PPI in adult male offspring. In contrast, a pyrogenic dose of poly I:C administered to pregnant rats on
Acknowledgements
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) and a grant from the Canadian Psychiatric Research Foundation, the CIHR Institute of Neurosciences, Mental Health and Addiction, the CIHR Research and Development Program and AstraZeneca Canada Inc. Marie-Eve Fortier was the recipient of a Studentship from the Fonds de la Recherche en Santé du Québec (FRSQ).
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