Chronic Interleukin-6 Exposure Alters Electrophysiological Properties and Calcium Signaling in Developing Cerebellar Purkinje Neurons in Culture

Abstract

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.

Interleukin-6 inhibits voltage-gated sodium channel activity of cultured rat spinal cord neurons

“…It has been reported that IL-6 acts on the target cells and promotes dimerisation of gp130, a signaltransducing subunit coupled with the IL-6 receptor (23,28), which is confirmed in our experiments (Fig. 1b and c).…”

IL-6 regulation of synaptic function in the CNS

“…Chronic exposure to IL-6 at a low concentration (1 ng/ml) enhanced Purkinje neurons spike firing, whereas chronic exposure to a higher concentration of IL-6 (10 ng/m) resulted in an inhibition of spike firing (Nelson et al, 2002). Chronic exposure to IL-6 also elevated resting Ca 2+ levels, increased the magnitude of intracellular Ca 2+ signals evoked by activation of group I metabotropic glutamate receptors, enhance Ca 2+ signaling induced by excitatory transmitters and membrane depolarization in the cultured Purkinje neurons (Nelson et al, 2004, 2002). All of these effects of IL-6 could significantly alter synaptic transmission involving the Purkinje neurons.…”

Identification and association of relationships between selected personal and environmental factors and formal components of temperament and strategies of coping with stress in asthmatic patients

“…According to the monocyte-T-lymphocyte hypothesis the immune system plays a key role in determining someone's personality and temperament, through synthesis, release and uptake of monoamines in the central nervous system [25,33,34]. Decreased or increased expression of synaptic plasticity, neurogenesis, and neuromodulation through basal ganglia, the frontal cortex and activity of the hypothalamus-pituitary axis (HPA) affect the limbic system and influence its various activations [26,27,35,36,37,38]. Thus, the complex of PEN traits and personality (temperament) is conditioned by many factors [39].…”