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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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Recovery of evoked quantal release after exposure of mouse ETA to BoNT/AQuantal content of the EPPin, calculated from mean amplitudes of mEPPins and EPPins (see Methods). Each point represents the mean of values from approximately 10 NMJs in a single muscle. Open symbol on ordinate shows mean value for 10 control muscles ± s.d.
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fig02: Recovery of evoked quantal release after exposure of mouse ETA to BoNT/AQuantal content of the EPPin, calculated from mean amplitudes of mEPPins and EPPins (see Methods). Each point represents the mean of values from approximately 10 NMJs in a single muscle. Open symbol on ordinate shows mean value for 10 control muscles ± s.d.

Mentions: To assess the changes in quantal release of ACh from the whole motor nerve terminal we used intracellular electrodes to record EPPins and mEPPins. From their amplitudes we calculated the quantal content (see Methods). These values are shown, as a function of time after BoNT/A injection, in Fig. 2. At NMJs in normal ETA muscles, the quantal content in our conditions was 57.9 (s.d. 26.8, n = 10). The quantal content fell to < 0.1 within 1–2 days after BoNT/A. The first NMJs where the QC had increased to > 1 were seen 12 days after injecting BoNT/A. By 6–7 weeks after BoNT/A the QC was about 60% (33.2, s.d. 13.1, n = 3) of normal and after 10–14 weeks was indistinguishable from normal (61.6, s.d. 15.2, n = 5). The mean EPPin amplitude was significantly correlated with the CMAP amplitude in the same muscle throughout the recovery period (r = 0.92, n = 53, P < 0.001). This implies that the experimental treatments used to record EPPs (μCTX, 4-Di-2-ASP) did not have a disproportionate effect on, for example, quantal release early in recovery. Mice of several strains were used in the course of this project (see Methods). No differences between the strains were observed in either the timing or extent of recovery.


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)

Recovery of evoked quantal release after exposure of mouse ETA to BoNT/AQuantal content of the EPPin, calculated from mean amplitudes of mEPPins and EPPins (see Methods). Each point represents the mean of values from approximately 10 NMJs in a single muscle. Open symbol on ordinate shows mean value for 10 control muscles ± s.d.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2538785&req=5

fig02: Recovery of evoked quantal release after exposure of mouse ETA to BoNT/AQuantal content of the EPPin, calculated from mean amplitudes of mEPPins and EPPins (see Methods). Each point represents the mean of values from approximately 10 NMJs in a single muscle. Open symbol on ordinate shows mean value for 10 control muscles ± s.d.
Mentions: To assess the changes in quantal release of ACh from the whole motor nerve terminal we used intracellular electrodes to record EPPins and mEPPins. From their amplitudes we calculated the quantal content (see Methods). These values are shown, as a function of time after BoNT/A injection, in Fig. 2. At NMJs in normal ETA muscles, the quantal content in our conditions was 57.9 (s.d. 26.8, n = 10). The quantal content fell to < 0.1 within 1–2 days after BoNT/A. The first NMJs where the QC had increased to > 1 were seen 12 days after injecting BoNT/A. By 6–7 weeks after BoNT/A the QC was about 60% (33.2, s.d. 13.1, n = 3) of normal and after 10–14 weeks was indistinguishable from normal (61.6, s.d. 15.2, n = 5). The mean EPPin amplitude was significantly correlated with the CMAP amplitude in the same muscle throughout the recovery period (r = 0.92, n = 53, P < 0.001). This implies that the experimental treatments used to record EPPs (μCTX, 4-Di-2-ASP) did not have a disproportionate effect on, for example, quantal release early in recovery. Mice of several strains were used in the course of this project (see Methods). No differences between the strains were observed in either the timing or extent of recovery.

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