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NMDARs can trigger intracellular cascades via Ca<jats:sup>2+<\/jats:sup> entry, however, also Ca<jats:sup>2+<\/jats:sup>-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by A<jats:italic>\u03b2<\/jats:italic>. We show that endogenous A<jats:italic>\u03b2<\/jats:italic> as well as exogenously added synthetic A<jats:italic>\u03b2<\/jats:italic> oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca<jats:sup>2+<\/jats:sup> chelator BAPTA or open-channel blockers MK-801 or memantine. A<jats:italic>\u03b2<\/jats:italic> increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. A<jats:italic>\u03b2<\/jats:italic>-induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca<jats:sup>2+<\/jats:sup> flux for synaptic degeneration by A<jats:italic>\u03b2<\/jats:italic>. We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of A<jats:italic>\u03b2<\/jats:italic> oligomers. Our data suggest that A<jats:italic>\u03b2<\/jats:italic> induces the activation of p38 MAPK and subsequent synaptic loss through Ca<jats:sup>2+<\/jats:sup> flux- and G protein-independent mechanisms.<\/jats:p>","DOI":"10.1038\/cddis.2015.160","type":"journal-article","created":{"date-parts":[[2015,6,18]],"date-time":"2015-06-18T12:47:18Z","timestamp":1434631638000},"page":"e1791-e1791","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["Calcium flux-independent NMDA receptor activity is required for A\u03b2 oligomer-induced synaptic loss"],"prefix":"10.1038","volume":"6","author":[{"given":"J H","family":"Birnbaum","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Bali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Rajendran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R M","family":"Nitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Tackenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,6,18]]},"reference":[{"key":"BFcddis2015160_CR1","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1002\/ana.410300410","volume":"30","author":"RD Terry","year":"1991","unstructured":"Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R et al. 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