Glial activation and central synapse loss, but not motoneuron degeneration, are prevented by the sigma-1 receptor agonist PRE-084 in the Smn2B/- mouse model of spinal muscular atrophy

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dc.contributor.authorCerveró Cebrià, Clàudia
dc.contributor.authorBlasco Carmona, Alba
dc.contributor.authorTarabal Mostazo, Olga
dc.contributor.authorCasanovas i Llorens, Anna
dc.contributor.authorPiedrafita Llorens, Lídia
dc.contributor.authorNavarro, Xavier
dc.contributor.authorEsquerda Colell, Josep
dc.contributor.authorCalderó i Pardo, Jordi
dc.date.accessioned2020-01-09T11:03:28Z
dc.date.available2020-01-09T11:03:28Z
dc.date.issued2018
dc.date.updated2020-01-09T11:03:31Z
dc.description.abstractSpinal muscular atrophy (SMA) is characterized by the loss of α-motoneurons (MNs) with concomitant muscle denervation. MN excitability and vulnerability to disease are particularly regulated by cholinergic synaptic afferents (C-boutons), in which Sigma-1 receptor (Sig1R) is concentrated. Alterations in Sig1R have been associated with MN degeneration. Here, we investigated whether a chronic treatment with the Sig1R agonist PRE-084 was able to exert beneficial effects on SMA. We used a model of intermediate SMA, the Smn2B/− mouse, in which we performed a detailed characterization of the histopathological changes that occur throughout the disease. We report that Smn2B/− mice exhibited qualitative differences in major alterations found in mouse models of severe SMA: Smn2B/− animals showed more prominent MN degeneration, early motor axon alterations, marked changes in sensory neurons, and later MN deafferentation that correlated with conspicuous reactive gliosis and altered neuroinflammatory M1/M2 microglial balance. PRE-084 attenuated reactive gliosis, mitigated M1/M2 imbalance, and prevented MN deafferentation in Smn2B/− mice. These effects were also observed in a severe SMA model, the SMNΔ7 mouse. However, the prevention of gliosis and MN deafferentation promoted by PRE-084 were not accompanied by any improvements in clinical outcome or other major pathological changes found in SMA mice.
dc.description.sponsorshipThis work was supported by grants from the Ministerio de Economía y Competitividad co-financed by FEDER (SAF2015-70801).
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1093/jnen/nly033
dc.identifier.idgrec027046
dc.identifier.issn0022-3069
dc.identifier.urihttp://hdl.handle.net/10459.1/67781
dc.language.isoeng
dc.publisherAmerican Association of Neuropathologists
dc.relationinfo:eu-repo/grantAgreement/MINECO//SAF2015-70801-R/ES/LOS AFERENTES SINAPTICOS DE TIPO C EN LAS MOTONEURONAS: IMPLICACIONES EN LA FISIOPATOLOGIA Y TERAPIA DE LA ESCLEROSIS LATERAL AMIOTROFICA Y DE LA ATROFIA MUSCULAR ESPINAL/
dc.relation.isformatofVersió postprint del document publicat a: https://doi.org/10.1093/jnen/nly033
dc.relation.ispartofJournal of Neuropathology and Experimental Neurology, 2018, vol. 77, num. 7, p. 577-597
dc.rights(c) American Association of Neuropathologists, 2018
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.subjectspinal muscular atrophy
dc.subjectMotoneuron
dc.subjectC-boutons
dc.subjectMicroglia
dc.subjectSigma-1 receptor
dc.subjectMotoneuron synaptic afferents
dc.subjectSmn2B/- mouse
dc.subjectSMNΔ7 mouse
dc.subjectSpinal muscular atrophy
dc.titleGlial activation and central synapse loss, but not motoneuron degeneration, are prevented by the sigma-1 receptor agonist PRE-084 in the Smn2B/- mouse model of spinal muscular atrophy
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
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