Kainate-glutamate interactions in rat cerebellar slices

Abstract

The effects of L-glutamate on the potency of kainate for stimulating guanosine 3',5'-cyclic monophosphate (cyclic GMP) accumulation and for killing neurones in incubated slices of immature (8-day) and adult rat cerebellum were investigated. L-glutamate did not potentiate the cyclic GMP responses to kainate in either the adult or the immature tissue (in contrast to a recent report), nor did it alter the pharmacological characteristics of this postsynaptic action of kainate in the immature cerebellum. Slices incubated for 2 h in the presence of L-glutamate displayed pronounced glial swelling and neuronal damage. These effects were concentration-dependent and neurones in the immature cerebellum proved to be about 10 times more susceptible than in the adult. None of the neuronal cell types appeared to be selectively vulnerable to the toxicity of glutamate. At the lower concentrations tested (300 microM in the immature tissue, 3 mM in the adult), neurotoxicity was largely restricted to regions near the cut edges of the slices, indicating that very effective mechanisms limit the diffusion of glutamate within the cerebellum. Kainate caused selective necrosis of Purkinje cells and inhibitory interneurones in slices of adult cerebellum at concentrations between 5 and 20 microM; 30 microM kainate, however, also affected granule cells. The neurotoxic potency of kainate towards all neuronal cell types was significantly lower in the immature cerebellum and was not enhanced by including glutamate in the incubation medium. Similarly, glutamate did not potentiate the neurotoxicity of kainate towards Purkinje cells and inhibitory interneurones or or towards granule cells in adult slices. It is concluded that the availability of glutamate is unlikely to be a factor which limits the neurotoxicity of kainate either in the immature or in the adult cerebellum. The increase in the neurotoxic potency of kainate with cerebellar maturation can be ascribed, more readily, to be developmentally-related appearance of kainate receptors.