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Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus. In rodents, soluble A\u03b2 oligomers (A\u03b2o) impair hippocampus-dependent learning and memory, promote dendritic spine loss, inhibit NMDA-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP), and promote synaptic depression (LTD), at least in part through activation of the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -CaM-dependent phosphatase calcineurin (CaN). Yet, questions remain regarding A\u03b2-dependent postsynaptic CaN signaling specifically at the synapse to mediate its synaptotoxicity. Here, we use pharmacologic and genetic approaches to demonstrate a role for postsynaptic signaling via A kinase-anchoring protein 150 (AKAP150)-scaffolded CaN in mediating A\u03b2-induced dendritic spine loss in hippocampal neurons from rats and mice of both sexes. In particular, we found that Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -permeable AMPA-type glutamate receptors (CP-AMPARs), which were previously shown to signal through AKAP-anchored CaN to promote both LTD and A\u03b2-dependent inhibition of LTP, are also required upstream of AKAP-CaN signaling to mediate spine loss via overexpression of APP containing multiple mutations linked to familial early-onset AD (FAD) and increased A\u03b2 production. In addition, we found that the CaN-dependent nuclear factor of activated T-cells (NFAT) transcription factors is required downstream to promote A\u03b2-mediated dendritic spine loss. Finally, we identified the E3-ubiquitin ligase Mdm2, which was previously linked to LTD and developmental synapse elimination, as a downstream NFAT target gene upregulated by A\u03b2 whose enzymatic activity is required for A\u03b2-mediated spine loss.\n                  <\/jats:p>","DOI":"10.1523\/eneuro.0175-23.2024","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T13:50:31Z","timestamp":1707400231000},"page":"ENEURO.0175-23.2024","source":"Crossref","is-referenced-by-count":22,"title":["Amyloid-\u03b2-Induced Dendritic Spine Elimination Requires Ca\n                    <sup>2+<\/sup>\n                    -Permeable AMPA Receptors, AKAP-Calcineurin-NFAT Signaling, and the NFAT Target Gene Mdm2"],"prefix":"10.1523","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2136-4933","authenticated-orcid":false,"given":"Tyler 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