Behavioral abnormalities of Zic1 and Zic2 mutant mice: Implications as models for human neurological disorders

Zic1 and Zic2 encode closely related zinc finger proteins expressed in dors al neural tube and its derivatives. In previous studies, we showed that the homozygous Zic1 null mutation (Zic1(-/-)) results in cerebellar malformati on with severe ataxia and that holoprosencephaly and spina bifida occur in homozygotes for Zic2 knockdown mutation (Zic2(kd/kd)). Since human ZIC2 hap loin-sufficiency is a cause of holoprosencephaly, the Zic2(kd/kd) mice are regarded as an animal model for holoprosencephaly in humans. In this study, the behavioral characteristics of the Zic1 and Zic2 mutant mice were inves tigated in heterozygotes (Zic1(-/+) or Zic2(kd/+)), and significant abnorma lities were found in the hanging, spontaneous locomotor activity, stationar y rod (Zic1(-/+)), acoustic startle response, and prepulse inhibition tests (Zic2(kd/+)). The abnormalities in the Zic1(-/+) mice may be explained in part by the hypotonia caused by hypoplasia of the cerebellar anterior vermi s, and these mice are regarded as a model of Joubert syndrome. In contrast, the sensorimotor gating abnormality in the Zic2(kd/+) mice may be attribut able to the presumed abnormality in the dorsomedial forebrain, which was st rongly affected in the Zic2(kd/kd) Mice. Zic2(kd/+) mice can serve as a mod el for diseases involving sensorimotor gating abnormalities, such as schizo phrenia.