Rat Mutants with Lateralized Rotational Behavior for Studying Disturbances in Cerebral Asymmetries and Their Involvement in Brain Disorders

The two circling rat mutants described in this review illustrate how genetic animal models may serve to study multifaceted brain functions and dysfunctions. The LEW/Ztm-ci2/ci2 and BH.7A/Ztm-ci3/ci3 rat mutants both exhibit lateralized circling and hyperactivity and thus provide models for studying disturbances in cerebral asymmetry and their involvement in brain disorders. In both mutants, the abnormal lateralization appears to be a consequence of imbalances of nigrostriatal dopaminergic functions. Furthermore, most likely as a consequence of alterations in dopaminergic activity, both rat mutants exhibit maladaptive behavior in tests of emotionality. However, apart from circling, hyperactivity, and maladaptive behavior in response to external stimuli, the LEW/Ztm-ci2/ci2 and BH.7A/Ztm-ci3/ci3 rat mutants differ in various aspects. Thus, ci2/ci2 rats exhibit cochlear and vestibular deficits, including deafness, abnormal swimming patterns, degeneration of hair cells in the inner ear, and morphological alterations in the cochlear and vestibular brain stem nuclei, whereas none of these deficits are observed in the ci3/ci3 mutant. Furthermore, functional and morphological retinal defects were determined in ci2/ci2 rats, so that we consider this rat mutant an interesting model of combined deafblindness and vestibular dysfunction such as occurring in Usher syndrome type 1. The affected gene in ci2/ci2 rats was identified as Myo15 , which encodes the unconventional myosin XVa. In �contrast, the candidate gene in ci3/ci3 rats is the D3 receptor gene (Drd3 ). Lack of D3 receptors has been shown to increase striatal dopamine levels and locomotor activity, so that the reduced D3 receptor expression found in ci3/ci3 mutant rats could explain the phenotype of these animals. Based on this phenotype and its antagonism by antidopaminergic drugs, we have proposed that ci3 mutants may serve as a model for Tourette syndrome.