In vitro neurotoxicity of excitatory acid analogues during cerebellar development

Abstract

The neurotoxic effects of the selective excitatory amino acid receptor agonists, quisqualate, kainate and N-methyl- d-aspartate, were studied in slice preparations of cerebellum from rats at different stages of postnatal development. With increasing age, (i) Purkinje cells became more vulnerable to kainate and quisqualate but remained insensitive to N-methyl- d-aspartate (up to 300 μM); (ii) Golgi cells became more sensitive to kainate, quisqualate and N-methyl- d-aspartate; (iii) granule cells became more sensitive to kainate, less sensitive to N-methyl- d-aspartate and remained unaffected by quisqualate (up to 100 μM), and (iv) basket and stellate cells and, up to 14 days of age, neurones of the deep cerebellar nuclei, became more vulnerable to kainate and quisqualate, but their sensitivity to N-methyl- d-aspartate stayed the same. The neurotoxicity of N-methyl- d-aspartate, but not that of kainate in 8-day-old cerebellar slices was prevented by 2-amino-5-phosphonovaleric acid; tetrodotoxin did not affect the toxicity of the agonists in 8-day-old or adult slices. The results with kainate are consistent with other studies indicating an insensitivity of the immature brain to its neurotoxic effects, but suggest that this property is not a peculiarity of kainate. Alterations in excitatory potency can explain some of the observed developmental changes. However, other observations cannot readily be accounted for on the basis of either changes in excitatory potency, the functional maturation of cerebellar circuits, changes in synaptic density, or the developmental appearance of Ca 2+ channels in susceptible cells, suggesting that additional factors play an important role in the neurotoxic effects of the excitants.