Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature

Abstract

Abstract Genetic factors significantly influence the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully elucidated. Recent extensive genomic studies implicate the protocadherin related 15 (PCDH15) gene in the onset of psychiatric disorders such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene for Usher syndrome, which leads to visual and auditory impairments, our Pcdh15 homozygous deletion mice (Pcdh15-null) did not show observable structural abnormalities in either the retina or inner ear. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations aligned with symptoms observed in various psychiatric patients and certain psychiatric disease mouse models. Specifically, the hyperactivity may mirror manic episodes in BD. To achieve a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, enabling continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with those of wild-type mice (WT). However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.