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Recovery of mouse neuromuscular junctions from single and repeated injections of botulinum neurotoxin A.

Rogozhin AA, Pang KK, Bukharaeva E, Young C, Slater CR - J. Physiol. (Lond.) (2008)

Bottom Line: The effects of an injection of BoNT/A wear off after 3-4 months so repeated injections are often used.In addition, branching of the intramuscular muscular motor axons, the distribution of the NMJs and the structure of many individual NMJs remain abnormal.These findings highlight the plasticity of the mammalian NMJ but also suggest important limits to it.

View Article: PubMed Central - PubMed

Affiliation: Kazan State Medical Academy, Kazan, Russia 420012.

ABSTRACT
Botulinum neurotoxin type A (BoNT/A) paralyses muscles by blocking acetylcholine (ACh) release from motor nerve terminals. Although highly toxic, it is used clinically to weaken muscles whose contraction is undesirable, as in dystonias. The effects of an injection of BoNT/A wear off after 3-4 months so repeated injections are often used. Recovery of neuromuscular transmission is accompanied by the formation of motor axon sprouts, some of which form new synaptic contacts. However, the functional importance of these new contacts is unknown. Using intracellular and focal extracellular recording we show that in the mouse epitrochleoanconeus (ETA), quantal release from the region of the original neuromuscular junction (NMJ) can be detected as soon as from new synaptic contacts, and generally accounts for > 80% of total release. During recovery the synaptic delay and the rise and decay times of endplate potentials (EPPs) become prolonged approximately 3-fold, but return to normal after 2-3 months. When studied after 3-4 months, the response to repetitive stimulation at frequencies up to 100 Hz is normal. When two or three injections of BoNT/A are given at intervals of 3-4 months, quantal release returns to normal values more slowly than after a single injection (11 and 15 weeks to reach 50% of control values versus 6 weeks after a single injection). In addition, branching of the intramuscular muscular motor axons, the distribution of the NMJs and the structure of many individual NMJs remain abnormal. These findings highlight the plasticity of the mammalian NMJ but also suggest important limits to it.

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Changes in kinetic properties of EPPins during recovery from exposure of mouse ETA muscles to BoNT/AAll recordings show EPPins selected from trains of 100 stimuli (1 Hz). A, typical EPPs (14 superimposed) from uninjected muscles. Note minimal variation of amplitude or time course. B, superimposed EPPins from ETA injected 21 days previously. Note great variation of both amplitude and time course, and much smaller amplitude than in control. C and D, changes in mean value of EPPin rise time (C, ‘RT’) and decay time (D, ‘DT’) during recovery from BoNT/A. The total quantal content is shown in each graph for comparison. Note that the kinetic properties of the EPPin return to normal values when the total quantal content has only reached approximately one-third of its normal value. E, variable time courses of EPPins recorded from the same muscle fibre, 15 days after exposure to BoNT/A. EPPins of two quite distinct time courses could be recorded from this fibre. Examples of these are shown in F (fast EPPins), G (mixed time-course EPPins) and H (slow EPPins). A single response showing both fast and slow components is highlighted in G.
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fig10: Changes in kinetic properties of EPPins during recovery from exposure of mouse ETA muscles to BoNT/AAll recordings show EPPins selected from trains of 100 stimuli (1 Hz). A, typical EPPs (14 superimposed) from uninjected muscles. Note minimal variation of amplitude or time course. B, superimposed EPPins from ETA injected 21 days previously. Note great variation of both amplitude and time course, and much smaller amplitude than in control. C and D, changes in mean value of EPPin rise time (C, ‘RT’) and decay time (D, ‘DT’) during recovery from BoNT/A. The total quantal content is shown in each graph for comparison. Note that the kinetic properties of the EPPin return to normal values when the total quantal content has only reached approximately one-third of its normal value. E, variable time courses of EPPins recorded from the same muscle fibre, 15 days after exposure to BoNT/A. EPPins of two quite distinct time courses could be recorded from this fibre. Examples of these are shown in F (fast EPPins), G (mixed time-course EPPins) and H (slow EPPins). A single response showing both fast and slow components is highlighted in G.

Mentions: During the early stages of recovery of transmission, evoked synaptic potentials with an unusually slow time course were sometimes seen (Fig. 10). Some of these recalled the ‘giant’ or ‘slow’ spontaneous miniature potentials previously described by others (Thesleff & Molgo, 1983; Thesleff et al. 1983; Kim et al. 1984). In those earlier studies, changes in the time course of evoked events were not reported.


Recovery of mouse neuromuscular junctions from single and repeated injections of botulinum neurotoxin A.

Rogozhin AA, Pang KK, Bukharaeva E, Young C, Slater CR - J. Physiol. (Lond.) (2008)

Changes in kinetic properties of EPPins during recovery from exposure of mouse ETA muscles to BoNT/AAll recordings show EPPins selected from trains of 100 stimuli (1 Hz). A, typical EPPs (14 superimposed) from uninjected muscles. Note minimal variation of amplitude or time course. B, superimposed EPPins from ETA injected 21 days previously. Note great variation of both amplitude and time course, and much smaller amplitude than in control. C and D, changes in mean value of EPPin rise time (C, ‘RT’) and decay time (D, ‘DT’) during recovery from BoNT/A. The total quantal content is shown in each graph for comparison. Note that the kinetic properties of the EPPin return to normal values when the total quantal content has only reached approximately one-third of its normal value. E, variable time courses of EPPins recorded from the same muscle fibre, 15 days after exposure to BoNT/A. EPPins of two quite distinct time courses could be recorded from this fibre. Examples of these are shown in F (fast EPPins), G (mixed time-course EPPins) and H (slow EPPins). A single response showing both fast and slow components is highlighted in G.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2538785&req=5

fig10: Changes in kinetic properties of EPPins during recovery from exposure of mouse ETA muscles to BoNT/AAll recordings show EPPins selected from trains of 100 stimuli (1 Hz). A, typical EPPs (14 superimposed) from uninjected muscles. Note minimal variation of amplitude or time course. B, superimposed EPPins from ETA injected 21 days previously. Note great variation of both amplitude and time course, and much smaller amplitude than in control. C and D, changes in mean value of EPPin rise time (C, ‘RT’) and decay time (D, ‘DT’) during recovery from BoNT/A. The total quantal content is shown in each graph for comparison. Note that the kinetic properties of the EPPin return to normal values when the total quantal content has only reached approximately one-third of its normal value. E, variable time courses of EPPins recorded from the same muscle fibre, 15 days after exposure to BoNT/A. EPPins of two quite distinct time courses could be recorded from this fibre. Examples of these are shown in F (fast EPPins), G (mixed time-course EPPins) and H (slow EPPins). A single response showing both fast and slow components is highlighted in G.
Mentions: During the early stages of recovery of transmission, evoked synaptic potentials with an unusually slow time course were sometimes seen (Fig. 10). Some of these recalled the ‘giant’ or ‘slow’ spontaneous miniature potentials previously described by others (Thesleff & Molgo, 1983; Thesleff et al. 1983; Kim et al. 1984). In those earlier studies, changes in the time course of evoked events were not reported.

Bottom Line: The effects of an injection of BoNT/A wear off after 3-4 months so repeated injections are often used.In addition, branching of the intramuscular muscular motor axons, the distribution of the NMJs and the structure of many individual NMJs remain abnormal.These findings highlight the plasticity of the mammalian NMJ but also suggest important limits to it.

View Article: PubMed Central - PubMed

Affiliation: Kazan State Medical Academy, Kazan, Russia 420012.

ABSTRACT
Botulinum neurotoxin type A (BoNT/A) paralyses muscles by blocking acetylcholine (ACh) release from motor nerve terminals. Although highly toxic, it is used clinically to weaken muscles whose contraction is undesirable, as in dystonias. The effects of an injection of BoNT/A wear off after 3-4 months so repeated injections are often used. Recovery of neuromuscular transmission is accompanied by the formation of motor axon sprouts, some of which form new synaptic contacts. However, the functional importance of these new contacts is unknown. Using intracellular and focal extracellular recording we show that in the mouse epitrochleoanconeus (ETA), quantal release from the region of the original neuromuscular junction (NMJ) can be detected as soon as from new synaptic contacts, and generally accounts for > 80% of total release. During recovery the synaptic delay and the rise and decay times of endplate potentials (EPPs) become prolonged approximately 3-fold, but return to normal after 2-3 months. When studied after 3-4 months, the response to repetitive stimulation at frequencies up to 100 Hz is normal. When two or three injections of BoNT/A are given at intervals of 3-4 months, quantal release returns to normal values more slowly than after a single injection (11 and 15 weeks to reach 50% of control values versus 6 weeks after a single injection). In addition, branching of the intramuscular muscular motor axons, the distribution of the NMJs and the structure of many individual NMJs remain abnormal. These findings highlight the plasticity of the mammalian NMJ but also suggest important limits to it.

Show MeSH
Related in: MedlinePlus