The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition.

The chakragati (ckr) mouse, which was serendipitously created as a result of a transgenic insertional mutation, has been proposed as a model of aspects of schizophrenia. The mice exhibit circling, hyperactivity, reduced social interactions, and enlarged lateral ventricles, which parallel aspects of the pathophysiology of schizophrenia. Deficits in sensorimotor gating and processing of the relevance of stimuli are core features of schizophrenia, which underlie many of the symptoms presented. Measures of prepulse inhibition (PPI) and latent inhibition (LI) can assess sensorimotor gating and processing of relevance in both humans and animal models. We investigated PPI of acoustic startle and LI of aversive conditioning in wild-type, heterozygous, and ckr mice. The ckr mice, which are homozygous for the transgene insertion, but not heterozygous littermates, showed impaired PPI in the absence of any difference in acoustic startle amplitude and showed deficits in LI of conditioning of a light stimulus to footshock, measured as suppression of licking for water in water-restricted mice. Together with the previous evidence for hyperactivity, reduced social interactions, and enlarged lateral ventricles, these data lend further support to the suggestion that the ckr mouse has utility as an animal model of aspects of schizophrenia.

The chakragati mouse: a mouse model for rapid in vivo screening of antipsychotic drug candidates.

The chakragati (ckr) mouse is a serendipitously discovered insertional transgenic mutant that exhibits circling and hyperactivity. Studies of social behavior, sensorimotor gating and ventricular anatomy suggest that the ckr mouse models aspects of schizophrenia. The underlying genetic and neurodevelopmental mechanisms remain to be elucidated but appear to result in a hemispheric asymmetry in striatal D(2)-like dopamine receptors. The circling is inhibited by administration of antipsychotic drugs and so lends itself to in vivo prospective screening for novel molecules with antipsychotic-like activity. Using the ckr mouse we have applied an in vivo first approach to screening for antipsychotic drug candidates. This offers the advantage of early indication of central nervous system bioavailability and potential toxicological concerns. Additionally, in vivo first screening in the ckr mouse is not biased by any particular neurotransmitter hypothesis of the disease, and so has the potential to identify compounds modifying the behavioral output by novel mechanisms of interaction with the underlying brain circuitry. Thus, in contrast to the classical strategy of hypothesis-driven in vitro screening for drugs fitting a "receptor model" of the disease, the ckr mouse screen has greater potential to identify lead molecules for a new generation antipsychotics with novel mechanisms of action.