Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring

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Abstract

Maternal exposure to viral infection has been associated with an increased risk of schizophrenia in the offspring, and it has been suggested that the maternal immune response may interfere with normal fetal brain development. Although studies in rodents have shown that perinatal viral infections can lead to neuropathological and behavioral abnormalities considered relevant to schizophrenia, it is not clear whether these consequences are due to the infection itself or to the maternal immune response to infection. We show that an induction of maternal immune stimulation without exposure to a virus by injecting pregnant dams with the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I:C) leads to abnormal behavioral and pharmacological responses in the adult offspring. As in schizophrenia, these offspring displayed excessive behavioral switching, manifested in the loss of latent inhibition and in rapid reversal learning. Consistent with the clinical pharmacology of schizophrenia, both deficits were alleviated by antipsychotic treatment. In addition, these offspring displayed increased sensitivity to the locomotor-stimulating effects of MK-801, pointing to developmental alterations of the dopaminergic and/or glutamatergic systems. Prenatal poly I:C administration did not produce learning deficits in classical fear conditioning, active avoidance, discrimination learning and water maze. These results show that the maternal immune response is sufficient to cause behavioral and pharmacological alterations relevant to schizophrenia in the adult offspring.

Introduction

Recent years have witnessed a growing emphasis on the contribution of neurodevelopmental factors to the pathophysiology of schizophrenia (Beckmann, 1999, Bogerts, 1993, Weinberger, 1995). Among environmental factors that may detrimentally affect neurodevelopment, prenatal exposure to viral infection has been implicated by several large epidemiological studies indicating that such exposure increases the risk of schizophrenia in adulthood (Adams et al., 1993, Izumoto et al., 1999, O’Callaghan et al., 1994, Torrey et al., 1988, Watson et al., 1984). Although the mechanisms whereby viral insults during neuro-ontogenesis can cause latent pathology in the CNS remain unknown, it has been suggested that the maternal immune response, and in particular pro-inflammatory cytokines released by the maternal immune system, may interfere with normal fetal brain development (Gilmore and Jarskog, 1997, Kirch, 1993, Marx et al., 2001, Nawa et al., 2000, Pearce, 2000, Pearce, 2001, Waltrip et al., 1984, Wright et al., 1993). The role of cytokines is underscored by findings that prenatal exposure to a variety of infections has been associated with an increased incidence of schizophrenia indicating that such an association may be mediated by a host response that is common to all infections (Gilmore and Jarskog, 1997, Marx et al., 2001, Nawa et al., 2000, Pearce, 2001).

Although studies in rodents have shown that perinatal viral infections can lead to neuropathological and behavioral abnormalities considered relevant to schizophrenia (Borrell et al., 2002, Engel et al., 2000, Fatemi et al., 1999, Pearce et al., 2000, Rothschild et al., 1999), it is not clear whether the consequences of prenatal infection are due to the infection itself or to the maternal immune response to infection. One approach to this question is to induce a maternal anti-viral-like response without exposure to a virus. This can be achieved by injecting pregnant dams with the synthetic double-stranded RNA, polyriboinosinic-polyribocytidilic acid (poly I:C). Systemic administration of poly I:C is commonly used to mimic viral exposure because it elicits immune responses analogous to those observed during viral infection, most notably by inducing the release of pro-inflammatory cytokines (Doukas et al., 1994, Katafuchi et al., 2003, Kimura et al., 1994, Pruett et al., 2003, Snell et al., 1997, Toth et al., 1990).

We have recently shown that the offspring of dams injected with poly I:C on gestational day (GD) 15, exhibited after puberty loss of latent inhibition (LI), the phenomenon whereby the behavioral control of stimuli is downgraded following their inconsequential preexposure (Zuckerman et al., 2001, Zuckerman et al., 2003, Zuckerman and Weiner, 2003). Disrupted LI is a well-established model of schizophrenia as rats and humans treated with amphetamine as well as acute schizophrenia patients show deficits in LI (Gray et al., 1991, Moser et al., 2000, Weiner, 2000, Weiner, 2003). Therefore, LI loss following prenatal poly I:C administration indicated that maternal immune response was sufficient to cause long term abnormalities potentially relevant to schizophrenia. This was supported by our findings that antipsychotic treatment restored LI in the adult poly I:C offspring, and that these rats exhibited excessive amphetamine-induced activity (Zuckerman et al., 2003), as well as by a recent report that prenatal poly I:C administration led to an additional schizophrenia-like deficit, loss of prepulse inhibition, in mice (Shi et al., 2003).

The present study sought to further validate the prenatal poly I:C model of induction as a model of schizophrenia, and in particular, the specificity of the cognitive deficits and response to drugs produced by this manipulation. For this end, we administered poly I:C on GD-15 or GD-17, a time during the proliferation and migration of limbic cortical neurons (Bayer, 1980, Bayer and Altman, 1991, Bayer et al., 1991), and tested the adult offspring in several behavioral tasks in addition to LI, namely, a position discrimination and reversal task, the Morris water maze task, and locomotor activity following the administration of the NMDA receptor antagonist MK-801. In addition, we assessed LI in two different procedures, namely, a conditioned emotional response (CER) procedure and a two-way active avoidance procedure, in order to evaluate the effects of prenatal poly I:C treatment on classical fear conditioning and operant aversive conditioning, respectively (in the nonpreexposed groups). Finally, we tested whether behavioral deficits induced by immune activation during pregnancy would be reversed by the atypical antipsychotic drug (APD) clozapine. Since administration on both GDs produced the same effects on LI (Experiment 1) and reversal (Experiment 2), in the following experiments poly I:C was administered only on GD-15.

Section snippets

Subjects

Male Wistar rats, 3 months old and weighing 350–400 g, bred in our laboratory, were housed four to a cage under reversed cycle lighting (lights on: 19:00–07:00) with ad lib food and water, except for one week prior to and during the LI in CER experiments (see below). All experimental protocols were carried out according to the guidelines of the Institutional Animal Care and Use Committee of Tel Aviv University.

Prenatal treatment

Wistar rats (Harlan Laboratories, Jerusalem) were mated at about an age of 3 months

Experiment 1 – The effects of prenatal poly I:C administration on GD-15 or GD-17 on LI and fear conditioning

There were no significant differences in the latencies to first lick, times to complete licks 1–50 and licks 51–75, and suppression ratios of the two control (prenatal saline) groups (n per group = 3 and 4), so their data were combined for the final analysis (n = 7 per group). The six experimental groups did not differ in the latency to first lick and in the times to complete licks 1–50 and licks 51–75 (prior to tone onset; all p’s > 0.05).

Fig. 1 presents the mean suppression ratios of the preexposed

Discussion

The present study showed that maternal immune activation induced by systemic poly I:C administration led to long term behavioral and pharmacological alterations in the offspring, including loss of LI, abnormally rapid reversal, and higher sensitivity to MK-801-locomotor enhancing effects.

As pointed out in Section 1, loss of LI is found in rats and normal humans treated with the dopamine releaser amphetamine (Gray et al., 1992a, Gray et al., 1992c, Thornton et al., 1996, Weiner et al., 1981,

Acknowledgements

We thank Novartis Switzerland for their gift of clozapine. This research was partly supported by the Adams Super-Center for Brain Studies, Tel-Aviv University, and the Israel Foundations Trustees award to L. Zuckerman.

References (93)

  • J.H. Gilmore et al.

    Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia [letter]

    Schizophrenia Research

    (1997)
  • Y. Izumoto et al.

    Schizophrenia and the influenza epidemics of 1957 in Japan

    Biological Psychiatry

    (1999)
  • M.H. Joseph et al.

    Modulation of latent inhibition in the rat by altered dopamine transmission in the nucleus accumbens at the time of conditioning

    Neuroscience

    (2000)
  • T. Katafuchi et al.

    Prolonged effects of polyriboinosinic:polyribocytidylic acid on spontaneous running wheel activity and brain interferon-alpha mRNA in rats: a model for immunologically induced fatigue

    Neuroscience

    (2003)
  • C.E. Marx et al.

    Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia

    Biological Psychiatry

    (2001)
  • R.J. McDonald et al.

    Context-specific interference on reversal learning of a stimulus-response habit

    Behavioural Brain Research

    (2001)
  • D.W. Miller et al.

    Effects of MK-801 on spontaneous and amphetamine-stimulated dopamine release in striatum measured with in vivo microdialysis in awake rats

    Brain Research Bulletin

    (1996)
  • B. Moghaddam

    Bringing order to the glutamate chaos in schizophrenia

    Neuron

    (2003)
  • P.C. Moser et al.

    The pharmacology of latent inhibition as an animal model of schizophrenia

    Brain Research Reviews

    (2000)
  • R.M. Murray et al.

    Genes, viruses and neurodevelopmental schizophrenia

    Journal of Psychiatric Research

    (1992)
  • R.D. Oades

    The role of noradrenaline in tuning and dopamine in switching between signals in the CNS

    Neuroscience and Biobehavioral Reviews

    (1985)
  • S.B. Pruett et al.

    Acute ethanol administration profoundly alters poly I:C-induced cytokine expression in mice by a mechanism that is not dependent on corticosterone

    Life Science

    (2003)
  • C. Rascle et al.

    Clinical features of latent inhibition in schizophrenia

    Schizophrenia Research

    (2001)
  • S.A. Rubin et al.

    Borna disease virus-induced hippocampal dentate gyrus damage is associated with spatial learning and memory deficits

    Brain Research Bulletin

    (1999)
  • E. Shadach et al.

    The latent inhibition model dissociates between clozapine, haloperidol, and ritanserin

    Neuropsychopharmacology

    (2000)
  • F.D. Toth et al.

    Interferon production by cultured human trophoblast induced with double stranded polyribonucleotide

    Journal of Reproductive Immunology

    (1990)
  • D. Vaitl et al.

    Latent inhibition and schizophrenia: pavlovian conditioning of autonomic responses

    Schizophrenia Research

    (2002)
  • R. Van den Bos et al.

    The involvement of the nucleus accumbens in the ability of rats to switch to cue-directed behaviors

    Life Science

    (1989)
  • D.R. Weinberger

    From neuropathology to neurodevelopment

    Lancet

    (1995)
  • I. Weiner et al.

    Chronic amphetamine and latent inhibition

    Behavioural Brain Research

    (1981)
  • I. Weiner et al.

    Amphetamine and the overtraining reversal effect

    Pharmacology Biochemistry and Behavior

    (1986)
  • I. Weiner et al.

    Simultaneous brightness discrimination and reversal: the effects of amphetamine administration in the two stages

    Pharmacology Biochemistry and Behavior

    (1986)
  • I. Weiner et al.

    Disruption of latent inhibition by acute administration of low doses of amphetamine

    Pharmacology Biochemistry and Behavior

    (1988)
  • I. Weiner et al.

    The latent inhibition model of schizophrenia: further validation using the atypical neuroleptic, clozapine

    Biological Psychiatry

    (1996)
  • I. Weiner et al.

    Haloperidol- and clozapine-induced enhancement of latent inhibition with extended conditioning: implications for the mechanism of action of neuroleptic drugs

    Neuropsychopharmacology

    (1997)
  • B.K. Yee et al.

    A comparison between the effects of medial septal lesions and entorhinal cortex lesions on performance of nonspatial working memory tasks and reversal learning

    Behavioural Brain Research

    (1998)
  • H. Yogev et al.

    Perseveration and over-switching in schizophrenia

    Schizophrenia Research

    (2003)
  • W.M. Abi-Saab et al.

    The NMDAmantagonist model for schizophrenia: promise and pitfalls

    Pharmacopsychiatry

    (1998)
  • W. Adams et al.

    Epidemiological evidence that maternal influenza contributes to the aetiology of schizophrenia. An analysis of Scottish, English, and Danish data

    British Journal of Psychiatry

    (1993)
  • F. Anscombe

    The disorder of consciousness in schizophrenia

    Schizophrenia Bulletin

    (1987)
  • I. Baruch et al.

    Differential performance of acute and chronic schizophrenics in a latent inhibition task

    Journal of Nervous and Mental Disease

    (1988)
  • S.A. Bayer

    Development of the Hippocampal Region in the Rat – 1. Neurogenisis Examined with 3H-Thymidine Autoradiography

    Journal of Comparative Neurology

    (1980)
  • S.A. Bayer et al.

    Neocortical development

    (1991)
  • S.A. Bayer et al.

    Cell migration in the rat embryonic neocortex

    Journal of Comparative Neurology

    (1991)
  • H. Beckmann

    Developmental malformations in cerebral structures of schizophrenic patients

    European Archives of Psychiatry and Clinical Neuroscience

    (1999)
  • B. Bogerts

    Recent advances in the neuropathology of schizophrenia

    Schizophrenia Bulletin

    (1993)
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    Present address: Center for Neurobiology and Behavior, Columbia University, 1051 Riverside Drive, New York, NY 10032-2695, USA.

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