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

• Published in: Psychopharmacologia Vol. 208; no. 4; pp. 531 - 543
• Main Authors: Meyer, Urs, Knuesel, Irene, Nyffeler, Myriel, Feldon, Joram
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2010; Springer; Springer Nature B.V
• Subjects: Adult and adolescent clinical studies; Animals; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cell Count - methods; Clozapine - administration & dosage; Clozapine - pharmacology; Clozapine - therapeutic use; Cognition & reasoning; Disease Models, Animal; Female; Hippocampus - drug effects; Hippocampus - physiology; Infections; Male; Medical sciences; Memory Disorders - chemically induced; Memory Disorders - complications; Memory Disorders - drug therapy; Memory Disorders - physiopathology; Memory, Short-Term - drug effects; Mice; Mice, Inbred C57BL; Neurogenesis - drug effects; Neurogenesis - physiology; Neuropharmacology; Neurosciences; Original Investigation; Pharmacology. Drug treatments; Pharmacology/Toxicology; Polynucleotides - adverse effects; Pregnancy; Pregnancy Complications, Infectious - immunology; Pregnancy Complications, Infectious - therapy; Prenatal development; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - drug therapy; Prenatal Exposure Delayed Effects - immunology; Prenatal Exposure Delayed Effects - psychology; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Psychotropic drugs; Rodents; Schizophrenia; Infection; Schizophrenia; Animal model; Cognition; Antipsychotic drugs; Hippocampus; Memory disorder; Dibenzodiazepine derivatives; Cognitive disorder; Atypical antipsychotic; Neuroleptic; Psychotropic; Central nervous system; Pharmacotherapy; Neurogenesis; Encephalon; Psychosis; Prenatal; Adult; Antagonist; Human; Drug; Clozapine; Injection; Chronic; D2 Dopamine receptor; Treatment; Working memory
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-009-1754-6

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.