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Abstract
Fusion of synaptic vesicles with the plasma membrane is mediated by the SNARE (soluble
NSF attachment receptor) proteins and is regulated by synaptotagmin (syt). There are
at least 17 syt isoforms that have the potential to act as modulators of membrane
fusion events. Synaptotagmin IV (syt IV) is particularly interesting; it is an immediate
early gene that is regulated by seizures and certain classes of drugs, and, in humans,
syt IV maps to a region of chromosome 18 associated with schizophrenia and bipolar
disease. Syt IV has recently been found to localize to dense core vesicles in hippocampal
neurons, where it regulates neurotrophin release. Here we have examined the ultrastructure
of cultured hippocampal neurons from wild-type and syt IV -/- mice using electron
tomography. Perhaps surprisingly, we observed a potential synaptic vesicle transport
defect in syt IV -/- neurons, with the accumulation of large numbers of small clear
vesicles (putative axonal transport vesicles) near the trans-Golgi network. We also
found an interaction between syt IV and KIF1A, a kinesin known to be involved in vesicle
trafficking to the synapse. Finally, we found that syt IV -/- synapses exhibited reduced
numbers of synaptic vesicles and a twofold reduction in the proportion of docked vesicles
compared to wild-type. The proportion of docked vesicles in syt IV -/- boutons was
further reduced, 5-fold, following depolarization.
Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.