P.1.h.045 Down syndrome model characterisation: gene expression after treatment with selective α5 GABAA modulator and quantification of metabolites

Ts65Dn mice are partially trisomic for the distal region of MMU16, which is homologous with the obligate segment of HSA21 triplicated in Down syndrome (DS). Ts65Dn mice are impaired in learning tasks that require an intact hippocampus. In order to investigate the neural basis of these deficits in this mouse model of Down syndrome, quantitative light and electron microscopy were used to compare the volume densities of neurons and synapses in the hippocampus of adult Ts65Dn (n=4) and diploid mice (n=4). Neuron density was significantly lower in the CA1 of Ts65Dn compared to diploid mice (p<0.01). Total synapse density was significantly lower in the dentate gyrus (DG; p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. The synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. When the data were broken down by synapse type, asymmetric synapse density was found to be significantly lower in the DG (p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice, while such a difference in symmetric synapse density was only present in the DG (p<0.01). The asymmetric synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to diploid mice, but there were no such significant differences in symmetric synapse-to-neuron ratios. These results suggest that impaired synaptic connectivity in the hippocampus of Ts65Dn mice underlies, at least in part, their cognitive impairment.