Functional repair of motor endplates after botulinum neurotoxin type A poisoning: Biphasic switch of synaptic activity between nerve sprouts and their parent terminals

Abstract

Blockade of acetylcholine release by botulinum neurotoxin type A at the neuromuscular junction induces the formation of an extensive network of nerve-terminal sprouts. By repeated in vivo imaging of N-(3-triethyl ammonium propyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide uptake into identified nerve endings of the mouse sternomastoid muscle after a single intramuscular injection of the toxin, inhibition of stimulated uptake of the dye at the terminals was detected within a few days, together with an increase in staining of the newly formed sprouts. After 28 days, when nerve stimulation again elicited muscle contraction, regulated vesicle recycling occurred only in the sprouts [shown to contain certain soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAREs) and to abut acetylcholine receptors] and not at the parent terminals. Therefore, only these sprouts could be responsible for nerve-muscle transmission at this time. However, a second, distinct phase of the rehabilitation process followed with a return of vesicle turnover to the original terminals, accompanied by an elimination of the by then superf luous sprouts. This extension and later removal of ''functional'' sprouts indicate their fundamental importance in the repair of paralyzed endplates, a finding with ramifications for the vital process of nerve regeneration.The ability of nerve endings at the neuromuscular junction to sprout after the potent blockade of neurotransmission by botulinum neurotoxin type A (BoTx͞A) is a striking example of synaptic plasticity (1-4). Although significant progress already has been made in identifying the factors triggering such outgrowth (see ref. 5), as well as that induced on, for example, partial denervation by nerve crush (1, 6), the significance of endplate remodeling in the intricate series of interactions between presynaptic and postsynaptic cells during recovery of transmission at paralyzed synapses has yet to be shown. The selective blockade of the regulated exocytosis of acetylcholine (ACh) by BoTx͞A after its intracellular proteolytic cleavage of synaptosomal-associated protein with a molecular mass of 25 kDa ref. 7 and 8) causes an unique and long-term eradication of synaptic activity, while, advantageously, avoiding removal of the nerve endings (9, 10). Despite the extent of the paralysis induced by this toxin, recovery of neurotransmission does occur eventually, as manifested in animal experiments (2, 11-13) and in the clinical treatment of dystonias involving involuntary movement of certain skeletal muscles (see ref. 14). Although BoTx͞A is known to promote nerve sprouting, it has remained unclear what the precise contribution, if any, these newly formed outgrowths make to the recovery from this initially dramatic, but ultimately temporary, paralysis.Limitations encountered in earlier studies on this fundamentally important question originated from the need to employ conventional histological techniques in vitro to excised tissues. These limitations have been overcome in our stu...

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

“…54 There is also evidence forncpuro_2007_279f3.eps subsequent compensatory nerve sprouting and the creation of extrajunctional synapses. [55][56][57][58] When exocytosis at the parent terminal eventually recovers, the nerves retract and endplate functioning returns to normal. 55,59 BTX-A administration has a similar effect on neuroeffector transmission in both smooth and striated muscle.…”

“…[55][56][57][58] When exocytosis at the parent terminal eventually recovers, the nerves retract and endplate functioning returns to normal. 55,59 BTX-A administration has a similar effect on neuroeffector transmission in both smooth and striated muscle. When BTX-A is administered to the bladder wall there is an increase in bladder capacity, with a reduction in incontinence episodes and symptoms of urgency.…”

Botulinumtoxin in der Urologie

“…Sprouting, am quergestreiften Muskel beschrieben, welches über mehrere Jahre bestehen bleibt (Borodic et al, 1994;de Paiva et al, 1999;Meunier et al, 2002) (Abb. 2.5…”

Intradetrusor versus suburothelial onabotulinumtoxinA injections for neurogenic detrusor overactivity: a pilot study

“…4,5 The clinical effect of botulinum toxin injection in the treatment of NDO has been established in several studies. [6][7][8] Further aspects of this form of treatment are currently under discussion, such as optimal dose, optimal dilution of botulinum toxin and the most effective administration technique (for example, bladder trigonum-saving technique versus injection into bladder trigonum).…”

“…4,5 The clinical effect of botulinum toxin injection in the treatment of NDO has been established in several studies. [6][7][8] Further aspects of this…”