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Chronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesis

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Abstract

Background

Converging evidence indicates that prenatal exposure to immune challenge can induce long-term cognitive deficits relevant to schizophrenia. Such cognitive impairments may be related to deficient hippocampal neurogenesis at adult age.

Objectives

In the present study, we sought evidence for the possibility that chronic treatment with the reference atypical antipsychotic drug clozapine may improve prenatal infection-induced cognitive dysfunctions by stimulating adult hippocampal neurogenesis.

Methods

This hypothesis was tested in a well-established mouse model of prenatal immune challenge which is based on prenatal administration of the viral mimic, polyriboinosinic–polyribocytidilic acid (PolyI:C).

Results

We found that maternal PolyI:C (5 mg/kg, i.v.) exposure on gestation day 17 led to significant spatial working memory impairment and reduced hippocampal neurogenesis in the resulting offspring at adult age. The latter effect was apparent in postmortem immunohistochemical analyses of the cell proliferation marker bromodeoxyuridine and the microtubule-associated protein doublecortin, a marker of newborn neuronal cells. Chronic (3 weeks) administration of clozapine (5 mg/kg/day, i.p.) significantly improved the prenatal PolyI:C-induced working memory deficits, while at the same time, it negatively affected working memory performance in adult offspring born to control mothers. These bidirectional cognitive effects of clozapine were not paralleled by concomitant effects on adult hippocampal neurogenesis.

Conclusions

Our findings do not support the hypothesis that the atypical antipsychotic drug clozapine may influence cognitive functions by acting on adult neurogenesis in the hippocampus, regardless of whether the drug is administered to subjects with or without a neurodevelopmental predisposition to adult neuropathology.

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Acknowledgments

The research presented in this study was partially supported by The Swiss National Science Foundation (SNSF) grant 310000-118284/1, by The Swiss Federal Institute of Technology (ETH Zurich) grant-11 07/03, and by a 2009 NARSAD Distinguished Investigator Award to Joram Feldon. We are extremely grateful to the Animal Services Department Schwerzenbach, Swiss Federal Institute of Technology, for their excellent animal husbandry and care.

Disclosure

All authors declare they have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology (ETH) Zurich, Schorenstrasse 16, 8603, Schwerzenbach, Switzerland

    Urs Meyer, Irene Knuesel, Myriel Nyffeler & Joram Feldon

  2. Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    Irene Knuesel

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  1. Urs Meyer
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  2. Irene Knuesel
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  3. Myriel Nyffeler
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  4. Joram Feldon
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Correspondence to Urs Meyer.

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Meyer, U., Knuesel, I., Nyffeler, M. et al. Chronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesis. Psychopharmacology 208, 531–543 (2010). https://doi.org/10.1007/s00213-009-1754-6

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  • DOI: https://doi.org/10.1007/s00213-009-1754-6

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