AbstractChronic central nervous system expression of the cytokine interleukin‐6 (IL‐6) is thought to contribute to the histopathological, pathophysiological, and cognitive deficits associated with various neurological disorders. However, the effects of chronic IL‐6 expression on neuronal function are largely unknown. Previous studies have shown that chronic IL‐6 exposure alters intrinsic electrophysiological properties and intracellular Ca2+ signalling evoked by ionotropic glutamate receptor activation in cerebellar Purkinje neurons. In the current study, using primary cultures of rat cerebellum, we investigated the effects of chronic IL‐6 exposure on metabotropic glutamate receptor (mGluR)‐activated Ca2+ signalling and release from intracellular Ca2+ stores. Chronic exposure (6–10 days) of Purkinje neurons to 500 units/mL IL‐6 resulted in elevated resting Ca2+ levels and increased intracellular Ca2+ signals evoked by the group I mGluR agonist (S)‐3,5‐dihydroxyphenylglycine (DHPG) compared to untreated control neurons. Chronic IL‐6 treatment also augmented Ca2+ signals evoked by brief 100 mm K+ depolarization, although to a lesser degree than responses evoked by DHPG. Depleting intracellular Ca2+ stores with sarcoplasmic‐endoplasmic reticulum ATPase inhibitors (thapsigargin or cyclopiazonic acid) or blocking ryanodine receptor‐dependent release from intracellular stores (using ryanodine) resulted in a greater reduction of DHPG‐ and K+‐evoked Ca2+ signals in chronic IL‐6‐treated neurons than in control neurons. The present data show that chronic exposure to elevated levels of IL‐6, such as occurs in various neurological diseases, alters Ca2+ signalling involving release from intracellular stores. The results support the hypothesis that chronic IL‐6 exposure disrupts neuronal function and thereby may contribute to the pathophysiology associated with many neurological diseases.