title: Pathogenicity of lupus anti-ribosomal P antibodies: role of cross-reacting neuronal surface P antigen in glutamatergic transmission and plasticity in a mouse model.
abstract: OBJECTIVE
  To assess whether autoantibodies against ribosomal P (anti-P), which are possibly pathogenic in neuropsychiatric systemic lupus erythematosus (NPSLE), alter glutamatergic synaptic transmission and to what extent the cross-reacting neuronal surface P antigen (NSPA) is involved.
  
  
  METHODS
  We analyzed glutamatergic transmission and long-term potentiation (LTP) mediated by AMPA receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) by field excitatory postsynaptic potential (EPSP) at the CA3-CA1 synapse. AMPAR activation by patch-clamp recordings in primary ventral spinal cord neurons was analyzed. In primary hippocampal neurons, NSPA distribution was assessed by double immunofluorescence, and intracellular calcium changes were evaluated using Fura-2 AM. NSPA-LacZ reporter-knockin mice expressing a truncated NSPA were used to assess NSPA expression pattern and function in the brain using β-galactosidase staining and comparative electrophysiology, calcium responses, and water maze memory tests.
  
  
  RESULTS
  NSPA was expressed in the brain in hippocampal CA1, dentate gyrus and ventral, but not dorsal, CA3 regions, encompassing postsynaptic regions and partial colocalization with NMDAR. Notably, NSPA-LacZ reporter-knockin mice showed impaired memory, and decreased NMDAR activity and LTP, with neurons insensitive to anti-P autoantibodies. Anti-P autoantibodies enhanced CA1 postsynaptic transmission, increasing AMPAR and NMDAR activity and leading to LTP abrogation after prolonged (20-minute) incubation.
  
  
  CONCLUSIONS
  Our findings indicate that the neuronal cell surface target of anti-P, NSPA, is involved in glutamatergic synaptic transmission and plasticity related to memory in the hippocampus, and mediates the deleterious effects of anti-P on these processes. Cognitive impairment, as well as other diffuse NPSLE manifestations, may develop when anti-P autoantibodies have access to brain regions coexpressing NSPA, AMPAR, and NMDAR.
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Fabián
authors.initials: F
authors.lastname: Segovia-Miranda
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Serrano
authors.affiliation: Universidad Andrés Bello, Santiago, Chile.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dyrda
authors.affiliation: Universidad Andrés Bello, Santiago, Chile.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Ampuero
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Retamal
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Marcela
authors.initials: M
authors.lastname: Bravo-Zehnder
authors.affiliation: Universidad Católica de Temuco, Temuco, Chile.
authors.forename: Jorge
authors.initials: J
authors.lastname: Parodi
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Pedro
authors.initials: P
authors.lastname: Zamorano
authors.affiliation: Regeneron Pharmaceuticals, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Valenzuela
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Loreto
authors.initials: L
authors.lastname: Massardo
authors.affiliation: Universidad Andrés Bello, Santiago, Chile.
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Zundert
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile, and Universidad de Magallanes, Punta Arenas, Chile.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile, and Universidad de Magallanes, Punta Arenas, Chile.
authors.forename: Alfonso
authors.initials: A
authors.lastname: González
mesh_terms: D000328:Adult; D000818:Animals; D000954:Antigens, Surface; D001323:Autoantibodies / Q000276:immunology*; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D056654:CA3 Region, Hippocampal / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D055879:Gene Knock-In Techniques; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D017774:Long-Term Potentiation; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008568:Memory; D051379:Mice; D009473:Neuronal Plasticity; D009474:Neurons / Q000276:immunology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012269:Ribosomal Proteins / Q000276:immunology* / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology; D009435:Synaptic Transmission; D055815:Young Adult
chemical_list: D000954:Antigens, Surface; D001323:Autoantibodies; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012269:Ribosomal Proteins; D018698:Glutamic Acid