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Pathogenicity of Lupus Anti–Ribosomal P Antibodies: Role of Cross‐Reacting Neuronal Surface P Antigen in Glutamatergic Transmission and Plasticity in a Mouse Model
Author(s) -
SegoviaMiranda Fabián,
Serrano Felipe,
Dyrda Agnieszka,
Ampuero Estibaliz,
Retamal Claudio,
BravoZehnder Marcela,
Parodi Jorge,
Zamorano Pedro,
Valenzuela David,
Massardo Loreto,
van Zundert Brigitte,
Inestrosa Nibaldo C.,
González Alfonso
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39081
Subject(s) - glutamatergic , ampa receptor , long term potentiation , neuroscience , synaptic plasticity , chemistry , excitatory postsynaptic potential , neurotransmission , nmda receptor , hippocampus , postsynaptic potential , microbiology and biotechnology , biology , glutamate receptor , receptor , biochemistry , inhibitory postsynaptic potential
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. Conclusion 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.