LP-BM5 virus-infected mice produce activating autoantibodies to the AMPA receptor

Autoantibodies to alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors may contribute to chronic hyperexcitability syndromes and neurodegeneration, but their origin is unclear We examined LP-BM5 murine le ukemia virus-infected mice, which manifest excitotoxic brain lesions and hy pergammaglobulinemia, for the presence of AMPA-receptor Ab's. Endogenous Ig G accumulated upon neurons in the neocortex and caudate/putamen of infected mice and interacted with native and recombinant AMPA-receptor subunits wit h the following relative abundance: GluR3 greater than or equal to GluR1 > GluR2 = GluR4, as determined by immunoprecipitation. In a radioligand assay , IgG preparations from infected mice specifically inhibited [H-3]AMPA bind ing to receptors in brain homogenates, an activity that was lost after prea dsorbing the IgG preparation to immobilized LP-BM5 virus. These IgGs also e voked currents when applied to hippocampal pyramidal neurons or to damaged cerebellar granule neurons. These currents could be blocked using any of se veral AMPA receptor antagonists. Thus, anti-AMPA-receptor Ab's can be produ ced as the result of a virus infection, in part through molecular mimicry. These Ab's may alter neuronal signaling and contribute to the neurodegenera tion observed in these mice, actions that may be curtailed by the use of AM PA-receptor antagonists.