Synapsin Ib disperses synaptic vesicles from the presynaptic terminal and accelerates synaptic fatigue

Synapsins are the most abundant phosphoproteins associated
with the membrane of synaptic vesicles. Multiple synapsin
isoforms exist, of which only synapsin IIa has been identified
as promoting clustering of synaptic vesicles in glutamatergic
neurons. This cluster supplies vesicles for release in parallel to
recycling, and thus plays a significant role in maintaining
transmission during periods of sustained activity. Dimerization of the synapsins was proposed to play a significant role in
interfacing between vesicles, by forming divalent vesiclebinding complexes that promote vesicle cross-linking. Synapsin Ib has been found to be incapable of binding directly to
vesicles, and on this basis we propose that it may prevent
vesicle cross-linking by heterodimerizing with other synapsins, thus disrupting vesicle clustering. We over-expressed
synapsin Ib in cultured hippocampal neurons using AAV
vectors and examined its effect on the morphology of
synapses, the quantity of vesicles in synaptic puncta and the
kinetics of short term depression, as an electrophysiological
indicator of vesicle recruitment. We found that synapsin
Ib overexpression causes a significant decrease in vesicle
density near the active zone, as well as a pronounced
widening of the synaptic puncta, consistent with
dispersal of the synaptic vesicles into the axon. In
concurrence, Fluorescence-Recovery-After-Photobleaching
of Synaptophysin-EGFP revealed that synapsin Ib increases
vesicle mobility. Finally, short-term synaptic depression
was accelerated, consistent with deficient supply of
vesicles to the release mechanism during sustained activity.
We conclude that synapsin Ib interferes with the ability of the
neuron to maintain a cluster of reserve vesicles near the active
zone.