title: Neuregulin-1 is concentrated in the postsynaptic subsurface cistern of C-bouton inputs to α-motoneurons and altered during motoneuron diseases.
abstract: C boutons are large, cholinergic, synaptic terminals that arise from local interneurons and specifically contact spinal α-motoneurons (MNs). C boutons characteristically display a postsynaptic specialization consisting of an endoplasmic reticulum-related subsurface cistern (SSC) of unknown function. In the present work, by using confocal microscopy and ultrastructural immunolabeling, we demonstrate that neuregulin-1 (NRG1) accumulates in the SSC of mouse spinal MNs. We also show that the NRG1 receptors erbB2 and erbB4 are presynaptically localized within C boutons, suggesting that NRG1-based retrograde signaling may occur in this type of synapse. In most of the cranial nuclei, MNs display the same pattern of NRG1 distribution as that observed in spinal cord MNs. Conversely, MNs in oculomotor nuclei, which are spared in amyotrophic lateral sclerosis (ALS), lack both C boutons and SSC-associated NRG1. NRG1 in spinal MNs is developmentally regulated and depends on the maintenance of nerve-muscle interactions, as we show after nerve transection experiments. Changes in NRG1 in C boutons were also investigated in mouse models of MN diseases: i.e., spinal muscular atrophy (SMNΔ7) and ALS (SOD1(G93A)). In both models, a transient increase in NRG1 in C boutons occurs during disease progression. These data increase our understanding of the role of C boutons in MN physiology and pathology.
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Gallart-Palau
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Tarabal
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Casanovas
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Sábado
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Correa
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Hereu
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain.
authors.forename: Lídia
authors.initials: L
authors.lastname: Piedrafita
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain josep.esquerda@mex.udl.cat jordi.caldero@mex.udl.cat.
authors.forename: Jordi
authors.initials: J
authors.lastname: Calderó
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Universitat de Lleida, Lleida, Catalonia, Spain josep.esquerda@mex.udl.cat jordi.caldero@mex.udl.cat.
authors.forename: Josep E
authors.initials: JE
authors.lastname: Esquerda
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D030161:Avian Proteins / Q000032:analysis / Q000502:physiology*; D002642:Chick Embryo; D002645:Chickens; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology; D020890:Neuregulin-1 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015388:Organelles / Q000737:chemistry*; D057907:Post-Synaptic Density / Q000737:chemistry* / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000737:chemistry* / Q000648:ultrastructure; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D066247:Receptor, ErbB-4; D012584:Sciatic Nerve / Q000293:injuries / Q000648:ultrastructure; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology / Q000254:growth & development
chemical_list: D030161:Avian Proteins; D066246:ErbB Receptors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C490582:NRG1 protein, Gallus gallus; C490581:Nrg1 protein, mouse; C587689:ERBB4 protein, human; C524056:Erbb2 protein, mouse; C587690:Erbb4 protein, mouse
keywords: amyotrophic lateral sclerosis; erbB receptors; interneurons; spinal cord ventral horn; spinal muscular atrophy