Preliminary evidence for reduced social interactions in Chakragati mutants modeling certain symptoms of schizophrenia.

Rodent models of schizophrenia provide powerful experimental tools for elucidating certain manifestations of the brain disease. The chakragati (ckr) mouse mutant, for instance, reproduces aberrant neuroanatomical and behavioral phenotypes observed in the corresponding human condition. To further investigate the utility of this mouse in the context of social behavior, we compared spontaneous behavioral activity and social interactions recorded during the subjective night among wild-type, heterozygous, and homozygous ckr mice. We found that both heterozygous and homozygous ckr animals failed to show appropriate norms of social behavior, including proximity, approach, huddling, and anogenital investigation in response to novel conspecifics. We further found that the anatomical distribution, topography, and connectivity of the neuropeptides oxytocin and vasopressin in the anterior hypothalamus did not differ among wild-type, heterozygous, or homozygous ckr animals. These latter findings suggest that although oxytocin and vasopressin influence social behavior, connectivity of such cells may not be phenotypically relevant for the observed social deficits seen in heterozygous and homozygous ckr mice. Collectively, ckr mice and their heterozygote kin are valuable experimental tools for pre-clinical studies involving disruptions of social behavior (e.g., social withdrawal).

Ventricular size mapping in a transgenic model of schizophrenia.

Genetically engineered mice have been generated to model a variety of neurological disorders. The chakragati (ckr) mouse is beginning to provide valuable insights into the structural brain changes underlying certain manifestations of schizophrenia. For instance, these mice show enlargement of the lateral ventricles, an abnormality frequently reported as a structural aberration in the schizophrenic brain. As neither the anatomical pattern nor the timing of this ventricular enlargement is known, we used magnetic resonance imaging (MRI) techniques to non-invasively visualize the development of the ventricular system in 5-, 10- and 30-day-old ckr pups. High-resolution MR images obtained from these mutants showed a progressive enlargement of the lateral ventricles, starting at day 5 of postnatal life. These emerging deficits were associated with abnormalities in mid-saggital corpus callosum area and thickness, particularly in 30-day-old adolescent animals. At this time of development, aberrant behaviors that mimic certain symptoms of schizophrenia also appeared in ckr mice suggesting that structural changes in ventricular size predates the onset of psychotic-like behaviors. These results are viewed as further indication that pre- and peri-natal disturbances of the ventricular system and adjacent neural regions may be important pathogenic factors in schizophrenia. Application of MRI to the ckr mouse is relatively new but has great potential for clarifying the relationship between brain structure changes and genetically induced vulnerabilities to psychoses.

The Vps33a gene regulates behavior and cerebellar Purkinje cell number.

A mutation in the Vps33a gene causes Hermansky-Pudlak Syndrome (HPS)-like-symptoms in the buff (bf) mouse mutant. The encoded product, Vps33a, is a member of the Sec1 and Class C multi-protein complex that regulates vesicle trafficking to specialized lysosome-related organelles. As Sec1 signaling pathways have been implicated in pre-synaptic function, we examined brain size, cerebellar cell number and the behavioral phenotype of bf mutants. Standardized behavioral tests (SHIRPA protocols) demonstrated significant motor deficits (e.g., grip strength, righting reflex and touch escape) in bf mutants, worsening with age. Histological examination of brain revealed significant Purkinje cell loss that was confirmed with staining for calbindin, a calcium binding protein enriched in Purkinje cells. This pathologic finding was progressive, as older bf mutants (13-14 months) showed a greater attrition of neurons, with their cerebella appearing to be particularly reduced (approximately 30%) in size relative to those of age-matched-control cohorts. These studies suggest that loss of Purkinje neurons is the most obvious neurological atrophy in the bf mutant, a structural change that generates motor coordination deficits and impaired postural phenotypes. It is conceivable therefore that death of cerebellar cells may also be a clinical feature of HPS patients, a pathological event which has not been reported in the literature. In general, the bf mutant may be a potentially new and useful model for understanding Purkinje cell development and function.