Possible dysfunction of ionotropic glutamate receptors in cerebellum of epileptic E1 mouse brain

Abstract

Binding of [ 3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) to an ion channel domain on the N -methyl- d-aspartate (NMDA)-sensitive subclass of brain glutamate (Glu) receptors was highest in the hippocampus of the hereditary epileptogenic mutant E1 as well as its parent ddY strain mice, when determined before and at equilibrium in the presence of 3 different agonists at the respective domains on the NMDA receptor complex, including Glu, glycine (Gly) and spermidine (SPD). Cerebellar [ 3H]MK-801 binding before equilibrium was significantly lower in E1 mice than in ddY mice, while the binding was not significantly different from each other in other brain structures of both strains of mice. Kinetic analysis revealed that the association rate was significantly lower with [ 3H]MK-801 binding in the cerebellum of E1 mice than of ddY mice. In contrast to ddY mice, furthermore, Gly failed to potentiate cerebellar [ 3H]MK-801 binding before equilibrium in E1 mice, with SPD being active in significantly inhibiting the binding. However, saturation analysis revealed that the affinity and density of cerebellar [ 3H]MK-801 binding at equilibrium in E1 mice were not significantly different from those in ddY mice. In addition, epileptogenic E1 mice had significantly higher levels of [ 3H]SPD binding in all brain structures examined than ddY mice, whereas [ 3H] dl-α-amino-3-hydroxy-5-methylisoxazole-4-propionate binding was significantly lower in the cerebellum of E1 mice than of ddY mice. These results suggest that dysfunction of cerebellar Glu receptors may be at least in part responsible for a variety of abnormal symptoms observed in epileptic E1 mice.