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Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation

2012-08-22Journal article Restricted access
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dc.contributor.authorDiógenes, Maria José
dc.contributor.authorDias, Raquel B.
dc.contributor.authorRombo, Diogo M.
dc.contributor.authorMiranda, Hugo Vicente
dc.contributor.authorMaiolino, Francesca
dc.contributor.authorGuerreiro, Patrícia
dc.contributor.authorNäsström, Thomas
dc.contributor.authorFranquelim, Henri G.
dc.contributor.authorOliveira, Luis M. A.
dc.contributor.authorCastanho, Miguel A. R. B.
dc.contributor.authorLannfelt, Lars
dc.contributor.authorBergström, Joakim
dc.contributor.authorIngelsson, Martin
dc.contributor.authorQuintas, Alexandre
dc.contributor.authorSebastião, Ana M.
dc.contributor.authorLopes, Luísa V.
dc.contributor.authorOuteiro, Tiago Fleming
dc.date.accessioned2013-10-25T15:39:03Z
dc.date.available2013-10-25T15:39:03Z
dc.date.issued2012-08-22
dc.description.abstractParkinson’s disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of -synuclein (a-syn) in various brain regions is themajorpathological hallmark. Indeed, themotorsymptomsinPDare causedby a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation onAMPAandNMDAreceptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposuretoa-synoligomersdrivestheincreaseofglutamatergicsynaptictransmission,preventingfurtherpotentiationbyphysiologicalstimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.por
dc.identifier.citationThe Journal of Neuroscience, 22 August 2012, 32(34): 11750-11762; doi: 10.1523/​JNEUROSCI.0234-12.2012por
dc.identifier.issn1529-2401
dc.identifier.urihttp://hdl.handle.net/10400.26/4825
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherSociety for Neurosciencepor
dc.relationMODULATION OF GLUTAMATE AMPA RECEPTORS BY ADENOSINE, IN PHYSIOLOGICAL AND HYPOXIC/ISCHEMIC CONDITIONS
dc.relationMODULATORY ROLE OF ADENOSINE AND BDNF UPON INHIBITORY SYNAPTIC TRANSMISSION AND PLASTICITY: CONSEQUENCES FOR EPILEPSY
dc.relationToward an understanding of protein glycation in Parkinson's disease: in vitro and in vivo studies of folding, aggregation and degradation pathways of alpha-synuclein, synphilin-1 and parkin under glycation conditions.
dc.relation.publisherversionhttp://www.jneurosci.org/content/32/34/11750.longpor
dc.subjectAlpha-synucleinpor
dc.subjecta-syn oligomerspor
dc.subjectParkinson's diseasepor
dc.titleExtracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activationpor
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMODULATION OF GLUTAMATE AMPA RECEPTORS BY ADENOSINE, IN PHYSIOLOGICAL AND HYPOXIC/ISCHEMIC CONDITIONS
oaire.awardTitleMODULATORY ROLE OF ADENOSINE AND BDNF UPON INHIBITORY SYNAPTIC TRANSMISSION AND PLASTICITY: CONSEQUENCES FOR EPILEPSY
oaire.awardTitleToward an understanding of protein glycation in Parkinson's disease: in vitro and in vivo studies of folding, aggregation and degradation pathways of alpha-synuclein, synphilin-1 and parkin under glycation conditions.
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F27761%2F2006/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F60386%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI%2F73430%2F2006/PT
oaire.citation.endPage11762por
oaire.citation.startPage11750por
oaire.citation.titleThe Journal of Neurosciencepor
oaire.citation.volume32por
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspor
rcaap.typearticlepor
relation.isProjectOfPublication3262733e-0519-4072-9045-0a2fbee56bbe
relation.isProjectOfPublication7309f68e-f908-4c6b-8030-c19ed2bb91be
relation.isProjectOfPublicationadc34721-a4f0-4f0a-8a7c-cf54687c08ab
relation.isProjectOfPublication.latestForDiscoveryadc34721-a4f0-4f0a-8a7c-cf54687c08ab

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