{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:48:11Z","timestamp":1791499691147,"version":"4.3.4"},"reference-count":67,"publisher":"Society for Neuroscience","issue":"15","license":[{"start":{"date-parts":[[2015,10,15]],"date-time":"2015-10-15T00:00:00Z","timestamp":1444867200000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2015,4,15]]},"abstract":"<jats:p>\n                    Botulinum neurotoxin type A (BoNT\/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests that the neurotoxic activity of BoNT\/A is not restricted to the periphery, but also reaches the CNS after retrograde axonal transport. Because BoNT\/A is internalized in recycling synaptic vesicles, it is unclear which compartment facilitates this transport. Using live-cell confocal and single-molecule imaging of rat hippocampal neurons cultured in microfluidic devices, we show that the activity-dependent uptake of the binding domain of the BoNT\/A heavy chain (BoNT\/A-Hc) is followed by a delayed increase in retrograde axonal transport of BoNT\/A-Hc carriers. Consistent with a role of presynaptic activity in initiating transport of the active toxin, activity-dependent uptake of BoNT\/A in the terminal led to a significant increase in SNAP25 cleavage detected in the soma chamber compared with nonstimulated neurons. Surprisingly, most endocytosed BoNT\/A-Hc was incorporated into LC3-positive autophagosomes generated in the nerve terminals, which then underwent retrograde transport to the cell soma, where they fused with lysosomes both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Blocking autophagosome formation or acidification with wortmannin or bafilomycin A\n                    <jats:sub>1<\/jats:sub>\n                    , respectively, inhibited the activity-dependent retrograde trafficking of BoNT\/A-Hc. Our data demonstrate that both the presynaptic formation of autophagosomes and the initiation of their retrograde trafficking are tightly regulated by presynaptic activity.\n                  <\/jats:p>","DOI":"10.1523\/jneurosci.3757-14.2015","type":"journal-article","created":{"date-parts":[[2015,4,15]],"date-time":"2015-04-15T12:37:33Z","timestamp":1429101453000},"page":"6179-6194","source":"Crossref","is-referenced-by-count":140,"title":["Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type 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