Chronic interleukin-6 exposure alters electrophysiological properties and calcium signaling in developing cerebellar purkinje neurons in culture.
The cytokine interleukin-6 (IL-6) is chronically expressed at elevated levels within the CNS in many neurological disorders and may contribute to the histopathological, pathophysiological, and cognitive deficits associated with such disorders. However, the effects of chronic IL-6 exposure on neuronal function in the CNS are largely unknown. Therefore using intracellular recording and calcium imaging techniques, we investigated the effects of chronic IL-6 exposure on the physiological properties of cerebellar Purkinje neurons in primary culture. Two weeks of exposure to 1,000 units/ml (U/ml) IL-6 resulted in altered electrophysiological properties of Purkinje neurons, including a significant reduction in action potential generation, an increase in input resistance, and an enhanced electrical response to the ionotropic glutamate receptor agonist, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) compared with untreated neurons. Lower concentrations of IL-6 (100 and 500 U/ml) had no effects on these electrophysiological parameters. However, neurons exposed to 500 U/ml chronic IL-6 resulted in significantly elevated resting levels of intracellular calcium as well as an increase in the intracellular calcium signal of Purkinje neurons in response to AMPA, effects not observed in neurons exposed to 1,000 U/ml chronic IL-6. Morphometric analysis revealed a lack of gross structural changes following chronic IL-6 treatment, such as in the number, size, and extent of dendritic arborization of Purkinje neurons in culture. Using immunohistochemistry, we found that cultured Purkinje neurons express both the IL-6 receptor and its intracellular signaling subunit, gp130, indicating that IL-6 may act directly on Purkinje neurons to alter their physiological properties. The present data show that chronic exposure to elevated levels of IL-6, such as occurs in various neurological diseases, produces alterations in several important physiological properties of Purkinje neurons and that these changes occur in the absence of neuronal toxicity, damage, or death. The results support the hypothesis that chronic IL-6 exposure can disrupt normal CNS function and thereby contribute to the pathophysiology associated with many neurological diseases.
Nelson
Thomas E
TE
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Ur
Christina L
CL
Gruol
Donna L
DL
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D050822:Cytokine Receptor gp130; D004594:Electrophysiology; D004622:Embryo, Mammalian; D006706:Homeostasis / Q000187:drug effects; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D015703:Antigens, CD; C494201:Il6st protein, rat; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002118:Calcium