title: Early and persistent abnormal decoding by glial cells at the neuromuscular junction in an ALS model.
abstract: Amyotrophic lateral sclerosis (ALS) is a late-onset neuromuscular disease characterized by progressive loss of motor neurons (MNs) preceded by neuromuscular junction (NMJ) denervation. Despite the importance of NMJ denervation in ALS, the mechanisms involved remain unexplored and ill defined. The contribution of glial cells in the disease has been highlighted, including axonal Schwann cell activation that precedes the decline of motor function and the onset of hindlimb paralysis. Because NMJ denervation occurs early in the process and that perisynaptic Schwann cells (PSCs), glial cells at the NMJ, regulate morphological stability, integrity, and repair of the NMJ, one could predict that PSC functions would be altered even before denervation, contributing to NMJ malfunctions. We tested this possibility using a slowly progressive model of ALS (SOD1(G37R) mice). We observed a normal NMJ organization at a presymptomatic stage of ALS (120 d), but PSC detection of endogenous synaptic activity revealed by intracellular Ca(2+) changes was enhanced compared with their wild-type littermates. This inappropriate PSC decoding ability was associated with an increased level of neurotransmitter release and dependent on intrinsic glial properties related to enhanced muscarinic receptor activation. The alteration of PSC muscarinic receptor functions also persists during the preonset stage of the disease and became dependent on MN vulnerability with age. Together, these results suggest that PSC properties are altered in the disease process in a manner that would be detrimental for NMJ repair. The impairments of PSC functions may contribute to NMJ dysfunction and ALS pathogenesis.
authors.affiliation: Département de neurosciences, Université de Montréal, Montréal, Québec H3C 3J7, Canada, Groupe de recherche sur le système nerveux central, Université de Montréal, Station centre-ville, Montréal, Québec H3C 3J7, Canada, and.
authors.forename: Danielle
authors.initials: D
authors.lastname: Arbour
authors.affiliation: Département de neurosciences, Université de Montréal, Montréal, Québec H3C 3J7, Canada, Groupe de recherche sur le système nerveux central, Université de Montréal, Station centre-ville, Montréal, Québec H3C 3J7, Canada, and.
authors.forename: Elsa
authors.initials: E
authors.lastname: Tremblay
authors.affiliation: Département de neurosciences, Université de Montréal, Montréal, Québec H3C 3J7, Canada, Groupe de recherche sur le système nerveux central, Université de Montréal, Station centre-ville, Montréal, Québec H3C 3J7, Canada, and.
authors.forename: Éric
authors.initials: É
authors.lastname: Martineau
authors.affiliation: Département de psychiatrie et de neurosciences, Université Laval, Québec G1V 0A6, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
authors.affiliation: Département de neurosciences, Université de Montréal, Montréal, Québec H3C 3J7, Canada, Groupe de recherche sur le système nerveux central, Université de Montréal, Station centre-ville, Montréal, Québec H3C 3J7, Canada, and richard.robitaille@umontreal.ca.
authors.forename: Richard
authors.initials: R
authors.lastname: Robitaille
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D051379:Mice; D009469:Neuromuscular Junction / Q000378:metabolism / Q000503:physiopathology*; D011976:Receptors, Muscarinic / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D055366:Synaptic Potentials
chemical_list: D011976:Receptors, Muscarinic; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium
keywords: SOD1; motor unit properties; muscarinic receptors; perisynaptic Schwann cells; synaptic transmission