Traffic of botulinum toxins A and E in excitatory and inhibitory neurons.
Botulinum neurotoxins (BoNTs), proteases specific for the SNARE proteins, are used to study the molecular machinery supporting exocytosis and are used to treat human diseases characterized by cholinergic hyperactivity. The recent extension of the use of BoNTs to central nervous system (CNS) pathologies prompted the study of their traffic in central neurons. We used fluorescent BoNT/A and BoNT/E to study the penetration, the translocation and the catalytic action of these toxins in excitatory and inhibitory neurons. We show that BoNT/A and BoNT/E, besides preferentially inhibiting synaptic vesicle recycling at glutamatergic relative to Gamma-aminobutyric acid (GABA)-ergic neurons, are more efficient in impairing the release of excitatory than inhibitory neurotransmitter from brain synaptosomes. This differential effect does not result from a defective penetration of the toxin in line with the presence of the BoNT/A receptor, synaptic vesicle protein 2 (SV2), in both types of neurons. Interestingly, exogenous expression of SNAP-25 in GABAergic neurons confers sensitivity to BoNT/A. These results indicate that the expression of the toxin substrate, and not the toxin penetration, most likely accounts for the distinct effects of the two neurotoxins at the two types of terminals and support the use of BoNTs for the therapy of CNS diseases caused by the altered activity of selected neuronal populations.
Verderio
Claudia
C
Department of Medical Pharmacology, University of Milano, Via Vanvitelli 32, 20129 Milano, Italy.
Grumelli
Carlotta
C
Raiteri
Luca
L
Coco
Silvia
S
Paluzzi
Silvio
S
Caccin
Paola
P
Rossetto
Ornella
O
Bonanno
Giambattista
G
Montecucco
Cesare
C
Matteoli
Michela
M
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001693:Biological Transport, Active; D001905:Botulinum Toxins / Q000493:pharmacokinetics* / Q000494:pharmacology; D019274:Botulinum Toxins, Type A / Q000493:pharmacokinetics* / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013572:Synaptic Vesicles / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D001224:Aspartic Acid; D005680:gamma-Aminobutyric Acid; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A; C096326:botulinum toxin type E