Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse

Abstract

Down syndrome (DS) is the most common genetic cause of mental retardation and affects many aspects of brain development. DS individuals exhibit an overall reduction in brain size with a disproportionately greater reduction in cerebellar volume. The Ts65Dn mouse is segmentally trisomic for the distal 12-15 Mb of mouse chromosome 16, a region that shows perfect conserved linkage with human chromosome 21, and therefore provides a genetic model for DS. In this study, high resolution magnetic resonance imaging and histological analysis demonstrate precise neuro- anatomical parallels between the DS and the Ts65Dn cerebellum. Cerebellar volume is significantly reduced in Ts65Dn mice due to reduction of both the internal granule layer and the molecular layer of the cerebellum. Granule cell number is further reduced by a decrease in cell density in the internal granule layer. Despite these changes in Ts65Dn cerebellar structure, motor deficits have not been detected in several tests. Reduction in granule cell density in Ts65Dn mice correctly predicts an analogous pathology in humans; a significant reduction in granule cell density in the DS cerebellum is reported here for the first time. The candidate region of genes on chromosome 21 affecting cerebellar development in DS is therefore delimited to the subset of genes whose orthologs are at dosage imbalance in Ts65Dn mice, providing the first localization of genes affecting a neuroanatomical phenotype in DS. The application of this model for analysis of developmental perturbations is extended by the accurate prediction of DS cerebellar phenotypes.

In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

“…1). Volumetric measurements obtained from high resolution T 2 images confirmed previous observations in Ts65Dn mice, and revealed a significant decrease in volume of the cerebellum (p < 0.05) [8,59].…”

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…Cerebellar hypoplasia has been previously identified in FXS patients (Mostofsky et al, 1998) and in other neurodevelopmental disorders such as autism and Downs' Syndrome (Shevell and Majnemer, 1996;Aylward et al, 1997;Baxter et al, 2000;Necchi et al, 2008). Additionally, DeLorey et al (1998) observed significant hypoplasia of the cerebellar vermal lobules in GABA A receptor β3 knockout mice.…”

Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model

“…Ts65Dn mice exhibit many of the central nervous system (CNS) phenotypes related to cognitive impairment in DS including abnormal dendritic spine density and structure, altered hippocampal structure with reduced number of neurons in the dentate gyrus and CA3 regions, and severe reductions in LTP (Belichenko et al, 2009;Belichenko, Kleschevnikov, Salehi, Epstein, & Mobley, 2007;Belichenko et al, 2004;Insausti et al, 1998;Kleschevnikov et al, 2004). Ts65Dn mice also show a reduction in cerebellum size, as well as the number of cerebral granule cells (Baxter, Moran, Richtsmeier, Troncoso, & Reeves, 2000). Ts65Dn mice have significant deficits in tasks that depend on the functional integrity of the hippocampal formation and associated neocortical circuits, including the Morris water maze spatial learning task and novel object recognition (Escorihuela et al, 1995;L.…”