Botulinum neurotoxin A impairs neurotransmission following retrograde transynaptic transport

Traffic. 2012 Aug;13(8):1083-9. doi: 10.1111/j.1600-0854.2012.01369.x. Epub 2012 May 9.


The widely used botulinum neurotoxin A (BoNT/A) blocks neurotransmission via cleavage of the synaptic protein SNAP-25 (synaptosomal-associated protein of 25 kDa). Recent evidence demonstrating long-distance propagation of SNAP-25 proteolysis has challenged the idea that BoNT/A remains localized to the injection site. However, the extent to which distant neuronal networks are impacted by BoNT/A retrograde trafficking remains unknown. Importantly, no studies have addressed whether SNAP-25 cleavage translates into structural and functional changes in distant intoxicated synapses. Here we show that the BoNT/A injections into the adult rat optic tectum result in SNAP-25 cleavage in retinal neurons two synapses away from the injection site, such as rod bipolar cells and photoreceptors. Retinal endings displaying cleaved SNAP-25 were enlarged and contained an abnormally high number of synaptic vesicles, indicating impaired exocytosis. Tectal injection of BoNT/A in rat pups resulted in appearance of truncated-SNAP-25 in cholinergic amacrine cells. Functional imaging with calcium indicators showed a clear reduction in cholinergic-driven wave activity, demonstrating impairments in neurotransmission. These data provide the first evidence for functional effects of the retrograde trafficking of BoNT/A, and open the possibility of using BoNT/A fragments as drug delivery vehicles targeting the central nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Botulinum Toxins, Type A / pharmacology*
  • Calcium Signaling
  • Rats
  • Rats, Long-Evans
  • Retinal Neurons / drug effects
  • Retinal Neurons / metabolism
  • Retinal Neurons / ultrastructure
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology
  • Synaptic Vesicles / drug effects
  • Synaptic Vesicles / metabolism*
  • Synaptic Vesicles / ultrastructure
  • Synaptosomal-Associated Protein 25 / antagonists & inhibitors*
  • Synaptosomal-Associated Protein 25 / metabolism


  • Snap25 protein, rat
  • Synaptosomal-Associated Protein 25
  • Botulinum Toxins, Type A
  • incobotulinumtoxinA