Mouse models of cognitive disorders in trisomy 21: a review.

Trisomy 21 (TRS21) is the most frequent genetic cause of mental retardation. Although the presence of an extra copy of HSA21 is known to be at the origin of the syndrome, we do not know which 225 HSA21 genes have an effect on cognitive processes. Mouse models of TRS21 have been developed using syntenies between HSA21 and MMU16, MMU10 and MMU17. Available mouse models carry extra fragments of MMU16 or of HSA21 that cover all of HSA21 (chimeric HSA21) or MMU16 (Ts16); some carry large parts of MMU16 (Ts65Dn, Ts1Cje, Ms1Cje), while others have reduced contiguous fragments covering the D21S17-ETS2 region or single transfected genes. This offers a nest design strategy for deciphering cognitive (learning, memory and exploration) and associated brain abnormalities involving each of these chromosomal regions. This review confirms the crucial but not exclusive contribution of the D21S17-ETS2 region encompassing 16 genes to cognitive disorders.

Pre-weaning sensorial and motor development in mice transpolygenic for the critical region of trisomy 21.

Trisomy 21 occurs every 1/800 births and is the most frequent genetic cause of mental retardation. Children with trisomy 21 show delayed sensorial and motor development as well as cognitive disorders. We selected a mouse model of trisomy 21 (TRS21): transgenic mice carrying extra copies of a HSA21 region corresponding to the D21S17-ETS2 region (previously referred to as "Down syndrome critical region 1"). Sensorial and motor development was measured in these partially transgenic mice, from birth to weaning. The four HSA21 regions contributed unequally to sensorial and motor development delay. The more centromeric region (230E8) modified 4 of the development indicators plus the size of the effect, indicated by partial eta(2)(eta(p)(2), reached a median value of 14.5%. The neighboring 141G6 region contributed to 5 developmental differences (eta(p)(2) median value 14%). The most telomeric region (285E6) only modified one development indicator. An extra copy of an HSA21 fragment (referred to here as the 152F7 region) induced modifications to 14 of the 18 indicators measured with a eta(2) median value reaching 20%. The results indicate a noticeable contribution of the 152F7 region to sensorial and motor development. The contribution of this region to cognitive functioning and its neurobiological basis has been already reported. This set of result suggests the location in the D21S17-ETS2 region of several genes playing crucial role in cognitive and developmental impairment observed in TRS21.

Functional analysis of genes implicated in Down syndrome: 2. Laterality and corpus callosum size in mice transpolygenic for Down syndrome chromosomal region -1 (DCR-1).

The association between atypical laterality and mental retardation has been reported several times, particularly in Down syndrome (DS). We investigated common genetic correlates of these components of the syndrome, examining direction (number of right paw entries in the Collins test) and degree (absolute difference between the number of right paw entries and the number of left paw entries) in mice that had incorporated extra-contiguous HSA21 fragments covering DCR-1 (Down Chromosomal Region-1). As corpus callosum size is substantially reduced in DS, and as the structure has been suspected of playing a role in atypical laterality, we also measured the corpus callosum in these mice. Extra copies of two regions (F7 and E6) have been associated with an atypical degree of laterality (strongly reduced degree). Extra copies of E8, G6 and E6 are also linked to the reduced size of the corpus callosum, indicating that the abnormal number of fibers linking the two hemispheres is not associated with atypical laterality in DS. Together, these results indicate that some of the genes involved in atypical laterality and in the reduced size of the corpus callosum in DS are present on DCR-1. An extra copy of F7 and, to a lesser extent, an extra copy of E6, are also associated with cognitive impairment. These results support the hypothesis of common genetic correlates in atypical laterality and mental retardation in DS.