Cognitive function in mice with segmental trisomy of human chromosome 21 Down Syndrome genes

Down Syndrome (DS) is a complex genetic disorder characterised by learning and memory impairments and age-related early-onset Alzheimer’s Disease. Sixty years ago, Lejeune et al. (1959) discovered that DS is caused by an extra copy of chromosome 21 (Hsa21). Despite a large body of research dedicated to the study of DS pathophysiology, the complex relationship between gene over-dosage, cognitive function and decline is still unclear. Genes on Hsa21 share synteny with orthologous regions on three mouse chromosomes (Mmu): Mmu16, Mmu17 and Mmu10. The primary aim of this thesis was to evaluate the contribution of the three orthologous regions to memory function in DS by studying genetically engineered mouse models, trisomic entirely and exclusively for one of the three regions: the Dp1Tyb, Dp3Yey and Dp2Yey. A battery of object-recognition memory tasks was used to assess different attributes and retention-spans of recognition memory in adult (12-13 months) and aged (18-20 months) mice of the three models. Performance in these tasks has been demonstrated to require glutamatergic activity within a network of medial temporal lobe structures, including the hippocampus. Dp1Tyb mice displayed age-independent impairments in recognition memory affecting selectively short-term memory processes. Dp3Yey mice displayed intact recognition memory. Dp2Yey mice displayed age-dependent impairments in recognition memory processes. At cellular level, the acquisition of new memories is proposed to rely on the regulation of synaptic transmission via changes in glutamate receptor expression. The secondary aim of this thesis was to identify biochemical mechanisms possibly associated to the pattern of memory performance of the three models. Glutamate receptor expression was thus assessed with western blots of hippocampal synaptosomes from the three models. Dp1Tyb mice displayed a downregulation of the postsynaptic scaffold protein PSD95 and an upregulation of the GluA1 AMPA receptor subunit, which has been previously implicated in short-term memory processes. Protein expression was unaltered in Dp3Yey mice. The Dp2Yey displayed an age-dependent downregulation of PSD95 and of the GluK5 kainate receptor subunit. This thesis studied for the first time the separate contribution of Hsa21 orthologues to recognition memory function and to glutamate receptor expression. Genes located on Mmu16 and 10 were found to be differentially important for memory processes, whereas no changes were observed with trisomy of genes on Mmu17. Potential candidate genes contributing to the behavioural and synaptic changes are considered and the contribution of these findings to understanding the complex genetic and functional changes observed in DS are discussed