Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome

Two animal models of Down syndrome (human trisomy 21) with segmental trisom y for ail (Ts65Dn) or part (Ts1Cje) of human chromosome 21-homologous regio n of mouse chromosome 16 have cognitive: and behavioral abnormalities. To c ompare these trisomies directly and to assess the phenotypic contribution o f the region of difference between them, Ts65Dn, Ts1Cje, and a new segmenta l trisomic (Ms1Ts65) for the region of difference (App to Sod1) have been g enerated as Littermates and tested in parallel. Although the performance of Ts1Cje mice in the Morris water maze is similar to that of Ts65Dn mice, th e reverse probe tests indicate that Ts65Dn is more severely affected. By co ntrast, the deficits of Ms1Ts65 mice are significantly less severe than tho se of Ts65Dn. Therefore, whereas triplication of Sod1 to Mx1 plays the majo r role in causing the abnormalities of Ts65Dn in the Morris water maze, imb alance of App to Sod1 also contributes to the poor performance. Ts65Dn mice are hyperactive and Ts1Cje mice are hypoactive; the activity of Ms1Ts65 mi ce is not significantly above normal. These findings indicate that genes in the Ms1Ts65 trisomic legion must interact with others in the Ts1Cje region to produce hyperactivity in Ts65Dn mice.