Elsevier

Behavioural Brain Research

Volume 181, Issue 2, 6 August 2007, Pages 270-277
Behavioural Brain Research

Research report
Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy

https://doi.org/10.1016/j.bbr.2007.04.016Get rights and content

Abstract

Maternal infection during pregnancy is a risk factor for some psychiatric illnesses of neurodevelopmental origin such as schizophrenia and autism. In experimental animals, behavioral and neuropathological outcomes relevant to schizophrenia have been observed in offspring of infected dams. However, the type of infectious agent used and gestational age at time of administration have varied. The objective of the present study was to compare the effects of prenatal challenge with different immune agents given at different time windows during gestation on behavioral outcomes in offspring. For this, pregnant rats were administered bacterial endotoxin (lipopolysaccharide, LPS), the viral mimic polyinosinic: polycytidylic acid (poly I:C), or turpentine, an inducer of local inflammation, at doses known to produce fever, at three different stages in pregnancy: embryonic day (E)10–11, E15–16 and E18–19. Prepulse inhibition of acoustic startle (PPI) was later measured in male adult offspring. PPI was significantly decreased in offspring after prenatal LPS treatment at E15–16 and E18–19. Intramuscular injection of pregnant dams with turpentine at E15–16 also decreased PPI in adult offspring. Maternal poly I:C administration had no significant effect on PPI in offspring. In contrast to prenatal LPS exposure, acute LPS administration to naive adult males had no effect on PPI. Thus, prenatal exposure both to a systemic immunogen and to local inflammation at brief periods during later pregnancy produced lasting deficits in PPI in rat offspring. These findings support the idea that maternal infection during critical windows of pregnancy could contribute to sensorimotor gating deficits in schizophrenia.

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).

References (62)

  • W.E. Magee et al.

    The liver as a site for interferon production in response to poly I:poly C

    Life Sci II

    (1972)
  • U. Meyer et al.

    Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia

    Neurosci Biobehav Rev

    (2005)
  • U. Meyer et al.

    Immunological stress at the maternal-foetal interface: a link between neurodevelopment and adult psychopathology

    Brain Behav Immun

    (2006)
  • K. Ozawa et al.

    Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia

    Biol Psychiatry

    (2006)
  • C.R. Pugh et al.

    Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning

    Brain Behav Immun

    (1998)
  • H.J. Romijn et al.

    At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby?

    Early Hum Dev

    (1991)
  • K.N. Shaw et al.

    Cyclooxygenase inhibition attenuates endotoxin-induced spatial learning deficits, but not an endotoxin-induced blockade of long-term potentiation

    Brain Res

    (2005)
  • N.L. Sparkman et al.

    Peripheral lipopolysaccharide administration impairs two-way active avoidance conditioning in C57BL/6J mice

    Physiol Behav

    (2005)
  • A.V. Turnbull et al.

    Mechanisms of activation of the pituitary-adrenal axis by tissue injury in the rat

    Psychoneuroendocrinology

    (1994)
  • M. van den Buuse et al.

    Estrogen increases prepulse inhibition of acoustic startle in rats

    Eur J Pharmacol

    (2001)
  • L. Alexopoulou et al.

    Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3

    Nature

    (2001)
  • H. Ashdown et al.

    The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia

    Mol Psychiatry

    (2006)
  • H. Bagalkote et al.

    Maternal influenza and schizophrenia

    Int J Ment Health

    (2001)
  • J. Bakos et al.

    Prenatal immune challenge affects growth, behavior, and brain dopamine in offspring

    Ann N Y Acad Sci

    (2004)
  • S.A. Bayer et al.

    Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat

    Neurotoxicology

    (1993)
  • A. Beishuizen et al.

    Endotoxin and the hypothalamo–pituitary–adrenal (HPA) axis

    J Endotoxin Res

    (2003)
  • D.L. Braff et al.

    Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies

    Psychopharmacology (Berl)

    (2001)
  • A.S. Brown et al.

    Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring

    Am J Psychiatry

    (2004)
  • A.S. Brown et al.

    Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring

    Am J Psychiatry

    (2005)
  • A.S. Brown et al.

    Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study

    Schizophr Bull

    (2000)
  • P.J. Brunton et al.

    Endogenous opioids and attenuated hypothalamic–pituitary–adrenal axis responses to immune challenge in pregnant rats

    J Neurosci

    (2005)
  • Cited by (0)

    1

    Tel.: +1 514 761 6131x3934; fax: +1 514 762 3034.

    2

    Tel.: +1 514 761 6131x4927; fax: +1 514 762 3034.

    View full text