Chronic interleukin-6 alters NMDA receptor-mediated membrane responses andenhances neurotoxicity in developing CNS neurons

Recent studies show that the cytokine interleukin-6 (IL-6) is expressed at elevated levels in the CNS in several disease states and contributes to the neuropathological process. The mechanisms through which IL-6 exerts its CN S effects are primarily unknown. We have investigated the pathophysiologica l effects of IL-6 on developing CNS neurons using a culture model system an d a chronic treatment paradigm. Here, we show, using current- and voltage-c lamp recordings, that chronic IL-6 treatment of developing cerebellar granu le neurons increases the membrane and current response to NMDA and that the se effects are the primary mechanism through which IL-6 produces an enhance d calcium signal to NMDA. We also show that calcium influx through voltage- sensitive calcium channels contributes to the enhanced calcium signal to NM DA in the IL-6-treated neurons in a developmentally regulated manner and th at the membrane depolarization to NMDA is more sensitive to the NMDA recept or antagonist ifenprodil in the IL-6-treated neurons compared with control neurons at a late developmental stage, consistent with a larger proportion of NMDA receptors containing the NMDAR2B subunit in the IL-6-treated neuron s. Additional studies show that IL-6 treatment reduces the number of granul e neurons in culture and enhances neurotoxicity involving NMDA receptors. T hese results support a pathological role for IL-6 in the CNS and indicate t hat NMDA receptor-mediated functions are likely to play a critical role in neuropathological changes observed in CNS diseases associated with elevated CNS levels of IL-6.