Kainic acid receptors and neurotoxicity in adult and immature rat cerebellar slices

Abstract

The neurotoxic actions of kainate were examined in incubated slices of adult and immature rat cerebellum using light- and electron-microscopy. In the adult, Purkinje cells and inhibitory interneurones became selectively necrotic at concentrations between 5 μM and 20 μM. At 30 μM, granule cells also became affected. In the immature cerebellum, at an age (8 days after birth) when the parallel fibres (thought to use glutamate as transmitter) are largely yet to be developed, selective toxicity was still evident but Purkinje cells and inhibitory interneurones were about 10-fold, and granule cells about 30-fold, less sensitive to kainate than in the adult. Kainate and other excitotoxins also increased cyclic GMP levels in cerebellar slices, apparently through the activation of excitatory amino acid receptors. In the adult tissue, the dose-cyclic GMP response curve to kainate was biphasic suggesting the presence of two components. The lower concentrations of kainate eliciting the first component mirrored those inducing selective necrosis of Purkinje cells and inhibitory interneurones while the second component correlated with necrosis of granule cells. Similar correlations applied to the immature cerebellum, but here kainate neurotoxicity appeared to be associated with the activation of receptor types different from those evident in the adult. It is suggested that kainate receptors, whose activation is associated with both neurotoxic damage and elevation of cyclic GMP levels, are located on all cell types in the adult cerebellum, with Purkinje cells and inhibitory interneurones displaying a higher sensitivity to kainate than granule cells. The lower sensitivity of immature cerebellum to the neurotoxic effect of kainate is probably due to lower levels of kainate receptors.