Abstract
Down syndrome (DS) is the most common genetic cause of intellectual disability, and arises from trisomy of human chromosome 21. Accumulating evidence from studies of both DS patient tissue and mouse models has suggested that synaptic dysfunction is a key factor in the disorder. The presence of several genes within the DS trisomy that are either directly or indirectly linked to synaptic vesicle (SV) endocytosis suggested that presynaptic dysfunction could underlie some of these synaptic defects. Therefore we determined whether SV recycling was altered in neurons from the Ts65Dn mouse, the best characterised model of DS to date. We found that SV exocytosis, the size of the SV recycling pool, clathrin-mediated endocytosis, activity-dependent bulk endocytosis and SV generation from bulk endosomes were all unaffected by the presence of the Ts65Dn trisomy. These results were obtained using battery of complementary assays employing genetically-encoded fluorescent reporters of SV cargo trafficking, and fluorescent and morphological assays of fluid-phase uptake in primary neuronal culture. The absence of presynaptic dysfunction in central nerve terminals of the Ts65Dn mouse suggests that future research should focus on the established alterations in excitatory / inhibitory balance as a potential route for future pharmacotherapy.
Highlights
Down syndrome (DS) is the most common genetic cause of intellectual disability, and arises from the presence of an extra copy of human chromosome 21 (Hsa21) [1]
synaptic vesicle (SV) acidification occurs with faster kinetics than endocytosis [46], and the recovery kinetics of the syppHluorin response after stimulation provides a readout of SV endocytosis rate
Cultures were stimulated with a train of 300 action potentials (10 Hz), which evoked a characteristic increase in syp-pHluorin fluorescence, followed by a recovery to baseline on termination of stimulation (Fig 1A and 1B)
Summary
Down syndrome (DS) is the most common genetic cause of intellectual disability, and arises from the presence of an extra copy of human chromosome 21 (Hsa21) [1]. Patients with DS display reductions in synapse number [2], decreased dendrite arborisation [3,4] and an imbalance between excitatory and inhibitory input [5,6], suggesting synaptic dysfunction is a key factor in the disorder. Altered presynaptic function could underlie some of these perturbations, since several key endocytosis genes are present on Hsa. Enlarged early endosomes are observed in DS brain from before birth [7]. This may result from perturbed synaptic vesicle (SV) recycling, since evidence is accumulating that some SV endocytosis modes intersect with classical endosomal trafficking routes [8].
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