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Here, we determined the impact of tau pathology on AMPAR expression, density, and subcellular distribution in the hippocampus of P301S mice using immunoblot, histoblot, and quantitative SDS-digested freeze-fracture replica labeling (SDS-FRL). Histoblot and immunoblot showed differential regulation of GluA1 and GluA2 in the hippocampus of P301S mice. The GluA2 subunit was downregulated in the hippocampus at 3 months while both GluA1 and GluA2 subunits were downregulated at 10 months. However, the total amount of GluA1-4 was similar in P301S mice and in age-matched wild-type mice. Using quantitative SDS-FRL, we unraveled the molecular organization of GluA1-4 in various synaptic connections at a high spatial resolution on pyramidal cell spines and interneuron dendrites in the CA1 field of the hippocampus in 10-month-old P301S mice. The labeling density for GluA1-4 in the excitatory synapses established on spines was significantly reduced in P301S mice, compared to age-matched wild-type mice, in the strata radiatum and lacunosum-moleculare but unaltered in the stratum oriens. The density of synaptic GluA1-4 established on interneuron dendrites was significantly reduced in P301S mice in the three strata. The labeling density for GluA1-4 at extrasynaptic sites was significantly reduced in several postsynaptic compartments of CA1 pyramidal cells and interneurons in the three dendritic layers in P301S mice. Our data demonstrate that the progressive accumulation of phospho-tau is associated with alteration of AMPARs on the surface of different neuron types, including synaptic and extrasynaptic membranes, leading to a decline in the trafficking and synaptic transmission, thereby likely contributing to the pathological events taking place in AD.<\/jats:p>","DOI":"10.3390\/ijms232113527","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T09:15:37Z","timestamp":1667553337000},"page":"13527","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice"],"prefix":"10.3390","volume":"23","author":[{"given":"Rocio","family":"Alfaro-Ruiz","sequence":"first","affiliation":[{"name":"Synaptic Structure Laboratory, Instituto de Investigaci\u00f3n en Discapacidades Neurol\u00f3gicas 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Ciencias M\u00e9dicas, Facultad de Medicina, Universidad Castilla-La Mancha, Campus Biosanitario, C\/Almansa 14, 02006 Albacete, Spain"},{"name":"Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L\u2019Hospitalet de Llobregat, Spain"},{"name":"Neuropharmacology and Pain Group, Neuroscience Program, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge, IDIBELL, 08907 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Esther","family":"Moreno-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Synaptic Structure Laboratory, Instituto de Investigaci\u00f3n en Discapacidades Neurol\u00f3gicas (IDINE), Departamento de Ciencias M\u00e9dicas, Facultad de Medicina, Universidad Castilla-La Mancha, Campus Biosanitario, C\/Almansa 14, 02006 Albacete, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Merch\u00e1n-Rubira","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8753-8249","authenticated-orcid":false,"given":"F\u00e9lix","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas, ISCIII, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6288-0571","authenticated-orcid":false,"given":"Jes\u00fas","family":"\u00c1vila","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain"},{"name":"Centro 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