title: Characterization of neuromuscular synapse function abnormalities in multiple Duchenne muscular dystrophy mouse models.
abstract: Duchenne muscular dystrophy (DMD) is an X-linked myopathy caused by dystrophin deficiency. Dystrophin is present intracellularly at the sarcolemma, connecting actin to the dystrophin-associated glycoprotein complex. Interestingly, it is enriched postsynaptically at the neuromuscular junction (NMJ), but its synaptic function is largely unknown. Utrophin, a dystrophin homologue, is also concentrated at the NMJ, and upregulated in DMD. It is possible that the absence of dystrophin at NMJs in DMD causes neuromuscular transmission defects that aggravate muscle weakness. We studied NMJ function in mdx mice (lacking dystrophin) and wild type mice. In addition, mdx/utrn(+/-) and mdx/utrn(-/-) mice (lacking utrophin) were used to investigate influences of utrophin levels. The three Duchenne mouse models showed muscle weakness when comparatively tested in vivo, with mdx/utrn(-/-) mice being weakest. Ex vivo muscle contraction and electrophysiological studies showed a reduced safety factor of neuromuscular transmission in all models. NMJs had ~ 40% smaller miniature endplate potential amplitudes compared with wild type, indicating postsynaptic sensitivity loss for the neurotransmitter acetylcholine. However, nerve stimulation-evoked endplate potential amplitudes were unchanged. Consequently, quantal content (i.e. the number of acetylcholine quanta released per nerve impulse) was considerably increased. Such a homeostatic compensatory increase in neurotransmitter release is also found at NMJs in myasthenia gravis, where autoantibodies reduce acetylcholine receptors. However, high-rate nerve stimulation induced exaggerated endplate potential rundown. Study of NMJ morphology showed that fragmentation of acetylcholine receptor clusters occurred in all models, being most severe in mdx/utrn(-/-) mice. Overall, we showed mild 'myasthenia-like' neuromuscular synaptic dysfunction in several Duchenne mouse models, which possibly affects muscle weakness and degeneration.
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Research Building S5-P, P.O. Box 9600 2300 RC, Leiden, The Netherlands.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: van der Pijl
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van Putten
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Research Building S5-P, P.O. Box 9600 2300 RC, Leiden, The Netherlands.
authors.forename: Erik H
authors.initials: EH
authors.lastname: Niks
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Research Building S5-P, P.O. Box 9600 2300 RC, Leiden, The Netherlands.
authors.forename: Jan J G M
authors.initials: JJ
authors.lastname: Verschuuren
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Aartsma-Rus
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Research Building S5-P, P.O. Box 9600 2300 RC, Leiden, The Netherlands.
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
mesh_terms: D000200:Action Potentials; D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials; D018763:Muscle Fatigue; D053580:Muscle Strength; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000503:physiopathology*; D011950:Receptors, Cholinergic / Q000378:metabolism; D012119:Respiration; D009435:Synaptic Transmission; D049411:Utrophin / Q000235:genetics
chemical_list: D016189:Dystrophin; D011950:Receptors, Cholinergic; D049411:Utrophin
keywords: acetylcholine receptor; electrophysiology; endplate; neuromuscular junction; synaptic transmission