title: Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy.
abstract: Mutations in peripheral myelin protein 22 (PMP22) result in the most common form of Charcot-Marie-Tooth (CMT) disease, CMT1A. This hereditary peripheral neuropathy is characterized by dysmyelination of peripheral nerves, reduced nerve conduction velocity, and muscle weakness. APMP22 point mutation in L16P (leucine 16 to proline) underlies a form of human CMT1A as well as the Trembler-J mouse model of CMT1A. Homozygote Trembler-J mice (Tr(J)) die early postnatally, fail to make peripheral myelin, and, therefore, are more similar to patients with congenital hypomyelinating neuropathy than those with CMT1A. Because recent studies of inherited neuropathies in humans and mice have demonstrated that dysfunction and degeneration of neuromuscular synapses or junctions (NMJs) often precede impairments in axonal conduction, we examined the structure and function of NMJs in Tr(J)mice. Although synapses appeared to be normally innervated even in end-stage Tr(J)mice, the growth and maturation of the NMJs were altered. In addition, the amplitudes of nerve-evoked muscle endplate potentials were reduced and there was transmission failure during sustained nerve stimulation. These results suggest that the severe congenital hypomyelinating neuropathy that characterizes Tr(J)mice results in structural and functional deficits of the developing NMJ.
authors.affiliation: From the Departments of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Scurry
authors.affiliation: From the Departments of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada.
authors.forename: Dante J
authors.initials: DJ
authors.lastname: Heredia
authors.affiliation: From the Departments of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Feng
authors.affiliation: From the Departments of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Gephart
authors.affiliation: From the Departments of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Hennig
authors.affiliation: From the Departments of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada. tgould@medicine.nevada.edu.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gould
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology*; D003964:Diaphragm / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000235:genetics; D006720:Homozygote; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009185:Myelin Proteins / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D009469:Neuromuscular Junction / Q000473:pathology / Q000648:ultrastructure; D020511:Neuromuscular Junction Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D017354:Point Mutation / Q000235:genetics
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human
keywords: Axonal degeneration; Hypomyelinating neuropathy; Myelination; Neuromuscular junction; Synaptic transmission; Terminal Schwann cell