Anti-P antibodies that impair memory perturb hippocampal glutamatergic receptor trafficking, synapse structure and...

Anti-ribosomal P protein autoantibodies (anti-P) are associated with psychosis and cognitive dysfunction in patients with systemic lupus erythematosus (SLE), yet the underlying mechanisms remain undefined, hindering targeted therapies. 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( +) immunized mice.

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.

Anti-P treatment of cultured neurons reduced GluN2A and GluA1 surface levels and impaired SEP-GluN2A and SEP-GluN2B recycling. Anti-P( +) mice showed spatial memory deficits persisting up to 24 days post-LPS, along with hippocampal alterations that include reduced levels of NMDAR, AMPAR, and PSD-95 in PSD fractions; increased membrane-associated PTPMEG; ~ 7% 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.

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-mediated cognitive dysfunction and may inform therapeutic strategies for neuropsychiatric SLE.