CEREBELLAR GRANULE NEURONS DEVELOP ELEVATED CALCIUM RESPONSES WHEN TREATED WITH INTERLEUKIN-6 IN CULTURE

In humans, elevated levels of cytokines are associated with several diseases (including HIV infection and Down Syndrome) that result in developmental abnormalities. Overexpression of interleukin-6 (IL-6) in the central nervous system has been shown to cause extensive neuronal abnormality in mice that becomes more evident with maturation. However, it is difficult to separate direct effects of IL-6 on the developing neurons of an intact animal from indirect effects involving effects on other cell types that possess cytokine receptors, such as microglia and astrocytes. We have found that IL-6 treatment of rat cerebellar granule neurons developing in the absence of other cell types in culture results in the persistence of large, depolarization or neurotransmitter-induced calcium transients that are normally observed only in immature neurons. The cause of this appears to be the persistence of a calcium-induced calcium release (CICR) component of the calcium response to stimulation. This basic abnormality in neuronal development may contribute to the developmental abnormalities associated with human syndromes that involve elevated cytokine levels.