Studies on neurotoxic mechanisms by excitotoxins

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The present study deals with modulation of gene transcription in the brain, in order to evaluate possible involvement of particular ionotropic receptor subtypes for L-glutamic acid in mechanisms underlying neuronal toxicity by excitotoxins. Transcription factors are nuclear proteins with high affinity for a particular core nucleotide sequence to modulate the activity of RNA polymerase II that is responsible for formation of mRNA from genomic DNA in the nucleus. The systemic administration of N-methyl-D-aspartic acid (NMDA) led to selective and drastic potentiation of DNA binding activity of the transcription factor activator protein-1 (AP1) in murine hippocampus. Frozen coronal sections were made with the aid of a cryostat, followed by punching out of the desired regions by a plastic capillary on dry ice under a binocular microscope. The potentiation was only seen in the dentate granule cells, but not in the CA1 and CA3 pyramidal cells. The potentiation in the dentate gyrus was transient with a peak at 2 h after administration and a decline within 4 h later, which occurred in a manner sensitive to antagonism by an NMDA channel blocker. Immunohistochemical analysis revealed that NMDA induced expression of both c-Jun and c-Fos proteins in the dentate gyrus, but not in the CA1 and CA3 subfields. By contrast, kainic acid (KA) induced drastic and prolonged potentiation of AP1 DNA binding in the CA1 and CA3 pyramidal layers in addition to dentate granule layers. The administration of KA but not NMDA led to marked potentiation of AP1 binding in areas neighboring but excluding pyramidal and granule layers. KA induced severe neuronal death in the CA1 and CA3 pyramidal layers without affecting dentate granular neurons. These results suggest that modulation of de novo synthesis of particular proteins may underlie mechanisms associated with neuronal cell death induced by excitotoxins.