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Botulinum Neurotoxin A Impairs Neurotransmission Following Retrograde Transynaptic Transport
Author(s) -
Restani Laura,
Novelli Elena,
Bottari David,
Leone Paola,
Barone Ilaria,
GalliResta Lucia,
Strettoi Enrica,
Caleo Matteo
Publication year - 2012
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2012.01369.x
Subject(s) - neurotransmission , synaptic vesicle , biology , cholinergic , neuroscience , exocytosis , postsynaptic potential , axoplasmic transport , microbiology and biotechnology , ribbon synapse , vesicle , endocrinology , biochemistry , receptor , membrane , secretion
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.