Maternal immune activation leads to behavioral and pharmacological changes 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.
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Present address: Center for Neurobiology and Behavior, Columbia University, 1051 Riverside Drive, New York, NY 10032-2695, USA.