Improved calcium utilization at motor nerve terminals exposed to botulinum neurotoxin in mice.
We examined the fail-safe responses against low-dose botulinum intoxication (botulinum neurotoxin serotype A; 0.05 ng/35 g body weight) in electrically activated in vitro phrenic nerve-diaphragm preparations, since sustained ventilation is critical for the prognosis of clinical botulinum intoxication. At 0, 1, 2 and 4 wks after the peritoneal injection of the toxin, both contractility and neurotransmitter release were measured. There was an increase in directly induced twitch force without affecting directly induced tetanus throughout the observation period. Indirectly induced twitch force decreased by 60% at 1 wk, which gradually recovered only during the 4-wk observation period. Spontaneous neurotransmitter release, evaluated as the frequency of miniature end plate potentials, was largely abolished 1 wk after the injection and recovered only slightly during the 4-wk period. The effects on spontaneous release were independent of medium Ca2+ concentration. Evoked release, evaluated as quantal content, was also mostly inhibited at 1 wk, but it recovered to approximately 50% of controls at 4 wks. The recovery of quantal content was more prominent at low medium Ca2+ concentration. These results indicated two functional fail-safe responses that compensate for the acute inhibitory effect of low dose of botulinum toxin on neuromuscular transmission; increased contractility of muscle, and improved efficiency of evoked quantum release. The increased contractility probably reflects remodeling of muscle fiber composition of the diaphragm. The improved efficiency of evoked quantum release probably involves remodeling of voltage-gated Ca2+ channels, intracellular Ca2+ store sites, or transmitter-releasing apparatuses.
Department of Pathogenetic Veterinary Science, the United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193 Japan. s13036@st.obihiro.ac.jp
Ryu
R
Fujikawa
Toshiaki
T
Ishii
Seiichi
S
Komori
Masakazu
M
Nishimura
D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D003964:Diaphragm / Q000294:innervation*; D004558:Electric Stimulation; D005260:Female; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D055369:Miniature Postsynaptic Potentials; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D010791:Phrenic Nerve / Q000187:drug effects* / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D020127:Recovery of Function; D013997:Time Factors
D019274:Botulinum Toxins, Type A; D002118:Calcium