A neurobehavioral screening of the ckr mouse mutant: implications for an animal model of schizophrenia.
A model of schizophrenia, the chakragati (ckr) mouse was serendipitously created as a result of a transgenic insertional mutation. The apparent loss-of-function of an endogenous gene produced mice that, when homozygous, displayed an abnormal circling behavior phenotype. To determine whether this phenotype could be corrected by atypical antipsychotics, we compared the effects of clozapine and olanzapine on rotational turns and hyperactivity. Both of these drugs successfully ameliorated circling behavior and hyperactivity in homozygous mice. The increased motor activity of these mutant mice was both qualitatively and quantitatively similar to that observed in wild-type animals treated with dizocilpine, an N-methyl-D-aspartate receptor antagonist that produces behaviors resembling positive symptoms of schizophrenia. Mice either homozygous or heterozygous for the mutation also displayed enlargement of the lateral ventricles, which was accompanied only in the homozygous genotype by a loss of individual myelinated axons in the striatum and agenesis of the corpus callosum. These structural brain deficits were selective in that the nigro-striatal dopamine system was normal in these homozygous mice. In addition, two types of interneurons in the neostriatum, namely those producing acetylcholine or nitric-oxide synthase were also devoid of significant structural abnormalities. These results indicate that the ckr mouse mutant could be used as a possible animal model to study the pathophysiology of schizophrenia and suggest possible strategies for treating the behavioral aspects of this brain disease.
Torres
German
G
Department of Neuroscience, New York College of Osteopathic Medicine of New York Institute of Technology, Old Westbury, NY 11568, USA.
Hallas
Brian H
BH
Vernace
Vita A
VA
Jones
Craig
C
Gross
Kenneth W
KW
Horowitz
Judith M
JM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001569:Benzodiazepines / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D005820:Genetic Testing / Q000379:methods; D020547:Lateral Ventricles / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D009154:Mutation; D000077152:Olanzapine; D012083:Renin / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology
D001569:Benzodiazepines; D016291:Dizocilpine Maleate; D012083:Renin; D003024:Clozapine; D000077152:Olanzapine