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dc.contributor.author
Trudler, Dorit  
dc.contributor.author
Sanz Blasco, Sara Isabel  
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Eisele, Yvonne S.  
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Ghatak, Swagata  
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Bodhinathan, Karthik  
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Akhtar, Mohd Waseem  
dc.contributor.author
Lynch, William P.  
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Pinã-Crespo, Juan C.  
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Talantova, Maria  
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Kelly, Jeffery W.  
dc.contributor.author
Lipton, Stuart A.  
dc.date.available
2023-09-20T17:15:33Z  
dc.date.issued
2021-03  
dc.identifier.citation
Trudler, Dorit; Sanz Blasco, Sara Isabel; Eisele, Yvonne S.; Ghatak, Swagata; Bodhinathan, Karthik; et al.; α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss ; Society for Neuroscience; Journal of Neuroscience; 41; 10; 3-2021; 2264-2273  
dc.identifier.issn
0270-6474  
dc.identifier.uri
http://hdl.handle.net/11336/212380  
dc.description.abstract
Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of a-synuclein (aSyn), are associated with disease progression, and have also been linked to other neurodegenerative diseases, including Lewy body dementia, Alzheimer's disease, and frontotemporal dementia. However, the effects of aSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that aSyn oligomers induce Ca21-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing aSyn manifest increased tonic release of glutamate in vivo. In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of aSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized aSyn can directly activate eNMDARs. In organotypic slices, oligomeric aSyn induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. When we expose human induced pluripotent stem cell-derived cerebrocortical neurons to aSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric aSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.  
dc.format
application/pdf  
dc.language.iso
eng  
dc.publisher
Society for Neuroscience  
dc.rights
info:eu-repo/semantics/restrictedAccess  
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/  
dc.subject
A-SYNUCLEIN OLIGOMERS  
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ASTROCYTIC GLUTAMATE  
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EXTRASYNAPTIC NMDARS  
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SYNAPTIC DAMAGE  
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Bioquímica y Biología Molecular  
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Medicina Básica  
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CIENCIAS MÉDICAS Y DE LA SALUD  
dc.title
α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss  
dc.type
info:eu-repo/semantics/article  
dc.type
info:ar-repo/semantics/artículo  
dc.type
info:eu-repo/semantics/publishedVersion  
dc.date.updated
2023-09-13T12:05:10Z  
dc.journal.volume
41  
dc.journal.number
10  
dc.journal.pagination
2264-2273  
dc.journal.pais
Estados Unidos  
dc.description.fil
Fil: Trudler, Dorit. Scintillon Institute; Estados Unidos. The Scripps Research Institute; Estados Unidos  
dc.description.fil
Fil: Sanz Blasco, Sara Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Sanford-burnham Medical Research Institute; Estados Unidos  
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Fil: Eisele, Yvonne S.. Sanford-burnham Medical Research Institute; Estados Unidos  
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Fil: Ghatak, Swagata. The Scripps Research Institute; Estados Unidos. Scintillon Institute; Estados Unidos  
dc.description.fil
Fil: Bodhinathan, Karthik. Sanford-burnham Medical Research Institute; Estados Unidos  
dc.description.fil
Fil: Akhtar, Mohd Waseem. Sanford-burnham Medical Research Institute; Estados Unidos  
dc.description.fil
Fil: Lynch, William P.. Kent State University; Estados Unidos  
dc.description.fil
Fil: Pinã-Crespo, Juan C.. Sanford-burnham Medical Research Institute; Estados Unidos  
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Fil: Talantova, Maria. Sanford-burnham Medical Research Institute; Estados Unidos  
dc.description.fil
Fil: Kelly, Jeffery W.. Kent State University; Estados Unidos  
dc.description.fil
Fil: Lipton, Stuart A.. Sanford-burnham Medical Research Institute; Estados Unidos  
dc.journal.title
Journal of Neuroscience  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1523/JNEUROSCI.1871-20.2020  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.jneurosci.org/content/41/10/2264