Maturation-dependent Modulation of Apoptosis in Cultured Cerebellar Granule Neurons by Cytokines and Neurotrophins

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Abstract
Immature cerebellar granule neurons die by apoptosis within 1 week in vitro unless maintained in depolarizing (high) concentrations of potassium (25 mM K+). Neurons allowed to survive and differentiate in high K+ medium for several days in vitro are still induced to undergo apoptosis when switched back to physiological (low) concentrations of K+ (5 mM). Here we have investigated the effects of various cytokines and growth factors in these two well‐defined paradigms of neuronal apoptosis. Tumour necrosis factor‐α, leukaemia inhibitory factor, ciliary neurotrophic factor, interleukin‐10 and interleukin‐13 delayed apoptosis and prolonged survival of cerebellar granule neurons maintained in low K+ medium. The effect observed required continuous exposure of the cultures to the cytokines and appeared not to involve modulation of Bcl‐2 protein expression. Brain‐derived neurotrophic factor accelerated neuronal death in low K+ medium. In contrast, when apoptosis of the neurons was precipitated by switching mature high K+ neurons to low K+ medium, neither tumour necrosis factor‐α, leukaemia inhibitory factor, ciliary neurotrophic factor, interleukin‐10 nor interleukin‐13 prevented apoptosis. When testing the cytokines and growth factors for their capacity to alter N‐methyl‐D‐aspartate receptor‐mediated excitotoxicity of differentiated cerebellar granule neurons, no significant effect was observed. These data appear to define a maturation‐dependent modulation of cerebellar granule cell survival by cytokines and neurotrophic factors that are expressed in a developmental pattern in the mammalian brain.

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