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dc.contributor.authorSalvany, Sara
dc.contributor.authorCasanovas i Llorens, Anna
dc.contributor.authorTarabal Mostazo, Olga
dc.contributor.authorPiedrafita Llorens, Lídia
dc.contributor.authorHernández, Sara
dc.contributor.authorSantafé Martínez, Manel
dc.contributor.authorSoto-Bernardini, María Clara
dc.contributor.authorCalderó i Pardo, Jordi
dc.contributor.authorSchwab, Markus H.
dc.contributor.authorEsquerda Colell, Josep
dc.date.accessioned2020-01-08T07:06:36Z
dc.date.available2020-03-26T23:11:28Z
dc.date.issued2019
dc.identifier.issn0892-6638
dc.identifier.urihttp://hdl.handle.net/10459.1/67775
dc.description.abstractC-type synaptic boutons (C-boutons) provide cholinergic afferent input to spinal cord motor neurons (MNs), which display an endoplasmic reticulum (ER)–related subsurface cistern (SSC) adjacent to their postsynaptic membrane. A constellation of postsynaptic proteins is clustered at C-boutons, including M2 muscarinic receptors, potassium channels, and s-1 receptors. In addition, we previously found that neuregulin (NRG)1 is associated with C-boutons at postsynaptic SSCs, whereas its ErbB receptors are located in the presynaptic compartment. Cbouton–mediated regulation of MN excitability has been implicated in MN disease, but NRG1-mediated functions and the impact of various pathologic conditions on C-bouton integrity have not been studied in detail. Here, we investigated changes inC-boutons after electrical stimulation,pharmacological treatment, and peripheral nerve axotomy. SSC-linked NRG1 clusters were severely disrupted in acutely stressedMNs and after tunicamycin-induced ER stress. In axotomized MNs, C-bouton loss occurred in concomitance with microglial recruitment and was prevented by the ER stress inhibitor salubrinal.Activatedmicroglia displayed apositive chemotaxis to C-boutons.Analysis of transgenicmice overexpressing NRG1 type I and type III isoforms in MNs indicated that NRG1 type III acts as an organizer of SSC-like structures, whereas NRG1 type I promotes synaptogenesis of presynaptic cholinergic terminals.Moreover,MN-derived NRG1 signals may regulate the activity of perineuronal microglial cells. Together, these data provide new insights into the molecular and cellular pathology of C-boutons in MN injury and suggest that distinct NRG1 isoform–mediated signaling functions regulate the complex matching between pre- and postsynaptic C-bouton elements.
dc.description.sponsorshipThe authors thank Klaus A. Nave (Max-Planck-Institute of Experimental Medicine, Göttingen, Germany) for advice and for supplying neuregulin-1–mutant mice; Jesús María López (Universidad Complutense de Madrid, Madrid, Spain), Ester Desfilis, and José Antonio Moreno for providing spinal cord samples from nonrodent animals; Anaïs Panosa and Xavier Calomarde (all from Universitat de Lleida−Institut de Recerca Biomèdica de Lleida) for technical support with confocal and electron microscopy; and the Serveis Científico-Tècnics Anima Facility of the University of Lleida for mouse care and housing. This work was supported by grants to J.E.E. and J.C. from the Spanish Ministerio de Economía y Competitividad cofinanced by the Fondo Europeo de Desarrollo Regional (FEDER; SAF2015-70801-R). S.S. holds a grant from Spanish Ministerio de Educación, Cultura, y Deporte (FPU). M.H.S. holds a Heisenberg Fellowship from the Deutsche Forschungsgemeinschaft (DFG) and acknowledges funding by a DFG research grant (SCHW741/4-1). The authors declare no conflicts of interest.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherFederation of American Societies for Experimental Biology
dc.relationMINECO/PN2013-2016/SAF2015-70801-R
dc.relation.isformatofVersió preprint del document publicat a: https://doi.org/10.1096/fj.201802329R
dc.relation.ispartofFASEB Journal, 2019, vol. 33, num. 7, p. 7833-7851
dc.rights(c) Federation of American Societies for Experimental Biology, 2019
dc.subjectSpinal cord
dc.subjectMotor neuron
dc.subjectC-bouton
dc.subjectNeuregulin
dc.subjectNerve transection
dc.subjectMicroglia
dc.titleLocalization and dynamic changes of neuregulin-1 at C-type synaptic boutons in association with motor neuron injury and repair
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2020-01-08T07:06:36Z
dc.identifier.idgrec028514
dc.type.versioninfo:eu-repo/semantics/submittedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.1096/fj.201802329R


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