Synaptic structural abnormalities in the Ts65Dn mouse model of down syndrome

Abstract

The Ts65Dn mouse is a genetic model for Down syndrome. Although this mouse shows abnormalities in cognitive function that implicate hippocampus as well as marked deficits in hippocampal long-term potentiation, the structure of the hippocampus has been little studied. We characterized synaptic structure in Ts65Dn and control (2N) mice, studying the hippocampus (fascia dentata, CA1) as well as the motor and somatosensory cortex, entorhinal cortex, and medial septum. Confocal microscopy was used to examine immunostained presynaptic boutons and to detail the structure of dendrites after Lucifer yellow microinjection. Both presynaptic and postsynaptic elements were significantly enlarged in Ts65Dn in all regions examined. The changes were detected at the youngest age examined (postnatal day 21) and in adults. In studies detailing the changes in fascia dentata and motor cortex, the enlargement of spines affected the entire population, resulting in the presence of spines whose volume was greatly increased. Electron microscopy confirmed that boutons and spines were enlarged and demonstrated abnormalities in the internal membranes of both. In addition, spine density was decreased on the dendrites of dentate granule cells, and there was reorganization of inhibitory inputs, with a relative decrease in inputs to dendrite shafts and an increase in inputs to the necks of spines. Taken together, the findings document widespread abnormalities of synaptic structure that recapitulate important features seen in Down syndrome. They establish the Ts65Dn mouse as a model for abnormal synapse structure and function in Down syndrome and point to the importance of studies to elucidate the mechanisms responsible for synapse enlargement.

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

“…These differences were statistically significant for Layers I, II and III (P \ 0.05). These results were in accordance with previous data obtained in other cortical areas in this DS model (Belichenko et al 2004). …”

“…A reduction in the number of asymmetric (excitatory) synapses per neuron has been shown in the different regions of the hippocampus, as well as in the temporal cortex of Ts65Dn mice (Kurt et al 2000). Moreover, the area occupied by synaptophysin (a reliable marker for synapses (Eastwood and Harrison 2001;Masliah et al 1990) is higher in these mice when compared with the euploids, suggesting an increase in the size of the synapse (Belichenko et al 2004). Finally, there is a clear redistribution of the inhibitory contacts on the dendrites of these mice: there is an increase in the density of contacts on spines and a decrease of those on dendritic shafts (Belichenko et al 2004).…”

“…Moreover, the area occupied by synaptophysin (a reliable marker for synapses (Eastwood and Harrison 2001;Masliah et al 1990) is higher in these mice when compared with the euploids, suggesting an increase in the size of the synapse (Belichenko et al 2004). Finally, there is a clear redistribution of the inhibitory contacts on the dendrites of these mice: there is an increase in the density of contacts on spines and a decrease of those on dendritic shafts (Belichenko et al 2004). Altogether, these results suggest an unbalanced level of inhibitory and excitatory inputs in the neocortex and the hippocampus in DS.…”

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

“…The most widely used DS mouse model, Ts65Dn mice, are trisomic for more than half of the mouse orthologs of genes on human chromosome 21 (59), whereas Ts1Cje mice carry a smaller segmental triplication included in Ts65Dn trisomy (60). That these two models display DS-characteristic growth retardation suggests that certain genes within the triplicated region are responsible, at least in part, for the phenotype (45,46,61). DYRK1A transgenic (Tg) mouse models were also made in an effort to reveal its role in DS.…”

“…6A). Ts65Dn mice exhibit neurodevelopmental delay and reduced body weight similar to that seen in individuals with DS (45,46). Because Hap1-KO mice suffer from growth retardation (5, 10), we proposed that in DS and its mouse models elevated DYRK1A pulls Dcaf7 away from Hap1, thereby influencing the normal function of Hap1 and thus contributing to the growth defect.…”