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Anti-P cross-react with a neuronal surface protein (NSPA), alter glutamatergic synaptic transmission and plasticity in hippocampal slices, and impair spatial memory in a short-term passive transfer mouse model. NSPA knockout mice display spatial memory deficit linked to reduced NMDAR activity and postsynaptic density (PSD) levels, along with an increased membrane-associated tyrosine phosphatase PTPMEG, suggesting disrupted glutamatergic receptor trafficking. Here, we investigated the acute effects of anti-P on receptor cell surface expression and trafficking in cultured hippocampal neurons and their long-term impact on hippocampal components and spatial memory in anti-P(\u2009+) immunized mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>NMDAR and AMPAR surface expression and NMDAR recycling were assessed in 21-24 DIV primary hippocampal neurons by immunofluorescence and FRAP using SEP-tagged receptors under the effects of rabbit anti-P IgG fractions. In vivo, female C57BL\/6 mice were immunized with recombinant P0 ribosomal protein to induce anti-P, followed by lipopolysaccharide (LPS) intraperitoneal administration to breach the blood-brain-barrier (BBB). Spatial memory was evaluated with a water maze memory flexibility test. Hippocampal synaptosomal membranes and PSD-enriched fractions were analyzed by immunoblotting. Neuronal density, microglia and dendritic architecture were evaluated using Cresyl Violet, Iba1 and Golgi staining, respectively.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Anti-P treatment of cultured neurons reduced GluN2A and GluA1 surface levels and impaired SEP-GluN2A and SEP-GluN2B recycling. Anti-P(\u2009+) mice showed spatial memory deficits persisting up to 24\u00a0days post-LPS, along with hippocampal alterations that include reduced levels of NMDAR, AMPAR, and PSD-95 in PSD fractions; increased membrane-associated PTPMEG;\u2009~\u20097% neuronal loss; higher number of microglia with reduced ramifications, and diminished dendritic width and spine density. Notably, increased PTPMEG levels were already detectable by day 10 post-LPS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Anti-P antibodies acutely impair glutamatergic receptor recycling and surface expression, while their long-term effects lead to sustained memory impairment associated with altered neuronal and microglial architecture, and PTPMEG increased levels preceding PSD protein loss. These findings provide mechanistic insight into anti-P\u2013mediated cognitive dysfunction and may inform therapeutic strategies for neuropsychiatric SLE.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s10020-025-01339-7","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T08:26:31Z","timestamp":1758875191000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Anti-P antibodies that impair memory perturb hippocampal glutamatergic receptor trafficking, synapse structure and microglia"],"prefix":"10.1186","volume":"31","author":[{"given":"Nicole","family":"D\u00edaz-Valdivia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Labarca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Retamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Espinoza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Venegas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Catenaccio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adely","family":"de la Pe\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela","family":"Ricca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Jara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Cort\u00e9s-D\u00edaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"P\u00e9rez-Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Barake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardita","family":"Medel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Herrera-Cid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Guzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bredford","family":"Kerr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Varas-Godoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela","family":"Bravo-Zehnder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loreto","family":"Massardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheril","family":"Tapia-Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"issue":"5","key":"1339_CR1","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1038\/sj.emboj.7600126","volume":"23","author":"G Ahmadian","year":"2004","unstructured":"Ahmadian G, Ju W, Liu L, Wyszynski M, Lee SH, Dunah AW, et al. 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