Chronic Interleukin-6 Alters NMDA Receptor-Mediated Membrane Responses and Enhances Neurotoxicity in Developing CNS Neurons

• Published in: The Journal of neuroscience Vol. 18; no. 24; pp. 10445 - 10456
• Main Authors: Qiu, Zhihua, Sweeney, Dan D, Netzeband, Jeffrey G, Gruol, Donna L
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 15-12-1998; Society for Neuroscience
• Subjects: Animals; Calcium Channels - drug effects; Calcium Channels - metabolism; Calcium Signaling - drug effects; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Survival - drug effects; Cells, Cultured; Cerebellum - drug effects; Cerebellum - metabolism; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Interleukin-6 - pharmacology; Membrane Potentials - drug effects; N-Methylaspartate - pharmacology; Neurons - drug effects; Neurons - metabolism; Patch-Clamp Techniques; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - metabolism; Time Factors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.18-24-10445.1998

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 CNS effects are primarily unknown. We have investigated the pathophysiological effects of IL-6 on developing CNS neurons using a culture model system and a chronic treatment paradigm. Here, we show, using current- and voltage-clamp recordings, that chronic IL-6 treatment of developing cerebellar granule neurons increases the membrane and current response to NMDA and that these effects are the primary mechanism through which IL-6 produces an enhanced calcium signal to NMDA. We also show that calcium influx through voltage-sensitive calcium channels contributes to the enhanced calcium signal to NMDA in the IL-6-treated neurons in a developmentally regulated manner and that the membrane depolarization to NMDA is more sensitive to the NMDA receptor 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 neurons. Additional studies show that IL-6 treatment reduces the number of granule neurons in culture and enhances neurotoxicity involving NMDA receptors. These results support a pathological role for IL-6 in the CNS and indicate that 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.