AUTOANTIBODIES TO NEURONAL GLUTAMATE RECEPTORS IN PATIENTS WITH PARANEOPLASTIC NEURODEGENERATIVE SYNDROME ENHANCE RECEPTOR ACTIVATION

Background: Paraneoplastic syndromes are ''remote'' complications of c ancer characterized clinically by neurological disease. The sera and c erebrospinal fluid (CSF) from patients with paraneoplastic neurologica l syndromes (PNS) frequently contain autoantibodies to ill-defined neu ronal antigens. We report here that neuronal glutamate receptors are t argets for autoantibodies found in the serum from some patients with w ell-characterized PNS. Materials and Methods: We have analyzed the ser um from seven patients with well-characterized PNS for the presence of autoreactive antibodies to non-NMDA glutamate receptor subunits. Auto antibodies were assessed using Western blot, immunohistochemistry, and immunocytochemistry. Whole-cell electrophysiological recordings were used to examine the effect of antibodies on glutamate receptors expres sed by cortical neurons in culture. Results: Six of seven patients' se rum contained autoantibodies to the non-NMDA glutamate receptor (GluR) subunits GluRI, GluR4, and/or GluR5/6. No patient had autoantibodies to GluR2, and only one patient exhibited weak immunoreactivity to GluR 3. Electrophysiological analysis demonstrated that the serum from four of the six GluR-antibody-positive patients enhanced glutamate-elicite d currents on cultured cortical neurons but had no effect on receptor function alone. Enhancement of glutamate-elicited currents was also pr oduced by affinity-purified antibody to GluR5. Conclusions: The occurr ence of autoantibodies to specific neuronal neurotransmitter subunits in the sera of patients with PNS and the ability of these autoantibodi es to modulate glutaminergic receptor function suggest that some paran eoplastic neurological injury could result from glutamate-mediated exc itotoxicity.