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


OBJECTIVE
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.
Meyer
Urs
U
Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland. urmeyer@ethz.ch
Knuesel
Irene
I
Nyffeler
Myriel
M
Feldon
Joram
J
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count / Q000379:methods; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D011119:Polynucleotides / Q000009:adverse effects; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000628:therapy*; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000523:psychology
D014150:Antipsychotic Agents; D011119:Polynucleotides; C049667:poly(rI).poly(dC); D003024:Clozapine