Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons

Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons

^*Consiglio Nazionale delle Ricerche Cellular and Molecular Pharmacology and “B. Ceccarelli” Centers, Department of Pharmacology, University of Milan, 20129 Milan, Italy; and ^‡Department of Biomedical Sciences, Consiglio Nazionale delle Ricerche Center for Biomembranes, University of Padua, 35121 Padua, Italy

Abstract

Tetanus neurotoxin causes the spastic paralysis of tetanus by blocking neurotransmitter release at inhibitory synapses of the spinal cord. This is due to the penetration of the toxin inside the neuronal cytosol where it cleaves specifically VAMP/synaptobrevin, an essential component of the neuroexocytosis apparatus. Here we show that tetanus neurotoxin is internalized inside the lumen of small synaptic vesicles following the process of vesicle reuptake. Vesicle acidification is essential for the toxin translocation in the cytosol, which results in the proteolytic cleavage of VAMP/synaptobrevin and block of exocytosis.

Footnotes

↵ † To whom reprint requests should be addressed. e-mail: MichelaM{at}farma.csfic.mi.cnr.it.
Vittorio Erspamer, Università degli Studi di Roma, Rome, Italy
Abbreviations: SV, synaptic vesicle; TeNT, tetanus neurotoxin; TR-TeNT, conjugate of Texas red and TeNT; CNS, central nervous system; Baf-A1, bafilomycin A1.