{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:37:41Z","timestamp":1790127461277,"version":"4.0.1"},"reference-count":48,"publisher":"Society for Neuroscience","issue":"10","license":[{"start":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T00:00:00Z","timestamp":1631232000000},"content-version":"vor","delay-in-days":231,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["DP1 DA041722"],"award-info":[{"award-number":["DP1 DA041722"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DA048882"],"award-info":[{"award-number":["R01 DA048882"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS086890"],"award-info":[{"award-number":["R01 NS086890"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG056259"],"award-info":[{"award-number":["R01 AG056259"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["RF1 AG057409"],"award-info":[{"award-number":["RF1 AG057409"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["K99\/R00 AG050764"],"award-info":[{"award-number":["K99\/R00 AG050764"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"accepted":{"date-parts":[[2020,12,28]]},"published-print":{"date-parts":[[2021,3,10]]},"abstract":"<jats:p>\n                    Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of \u03b1-synuclein (\u03b1Syn), 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 \u03b1Syn and its mechanism of synaptic damage remain incompletely understood. Here, we show that \u03b1Syn oligomers induce Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing \u03b1Syn manifest increased tonic release of glutamate\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of \u03b1Syn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized \u03b1Syn can directly activate eNMDARs. In organotypic slices, oligomeric \u03b1Syn 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 \u03b1Syn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric \u03b1Syn-induced damage in our model systems, thus meriting further study for its therapeutic potential.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>\n                    Loss of synaptic function and ensuing neuronal loss are associated with disease progression in Parkinson's disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. However, the mechanism of synaptic damage remains incompletely understood. \u03b1-Synuclein (\u03b1Syn) misfolds in PD\/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found that misfolded\/oligomeric \u03b1Syn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, \u03b1Syn oligomers directly activate eNMDARs, further contributing to damage. While the FDA-approved drug memantine has been reported to offer some benefit in PD\/LBD (Hershey and Coleman-Jackson, 2019), we find that the improved eNMDAR antagonist NitroSynapsin ameliorates \u03b1Syn-induced synaptic spine loss, providing potential disease-modifying intervention in PD\/LBD.\n                  <\/jats:p>","DOI":"10.1523\/jneurosci.1871-20.2020","type":"journal-article","created":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T14:48:35Z","timestamp":1611326915000},"page":"2264-2273","source":"Crossref","is-referenced-by-count":102,"title":["\u03b1-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss"],"prefix":"10.1523","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5835-3322","authenticated-orcid":false,"given":"Dorit","family":"Trudler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Sanz-Blasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3868-4327","authenticated-orcid":false,"given":"Yvonne S.","family":"Eisele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swagata","family":"Ghatak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Bodhinathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd Waseem","family":"Akhtar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Lynch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Pi\u00f1a-Crespo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Talantova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery W.","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart 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