Predominant expression of nuclear activator protein-1 complex with DNA binding activity following systemic administration of N-methyl-D-aspartate in dentate granule cells of murine hippocampus.

摘要

The systemic administration of N-methyl-D-aspartate (100 mg/kg, i.p.) resulted in preferential but transient expression of the transcription factor activator protein-1 in the granule cell layers of the dentate gyrus in the murine hippocampus by maximally 700% 1 h later, without markedly affecting that in the pyramidal cell layers of the CA1 and CA3 subfields for 4 h. The potentiation was completely prevented by prior administration of the N-methyl-D-aspartate channel blocker dizocilpine at 10 mglkg. By contrast, kainate (40 mg/kg, i.p.) potentiated activator protein-1 DNA binding in adjacent areas around the pyramidal and granule cell layers, in addition to potentiating that in neuronal cell layers of the CA1 and CA3 subfields and the dentate gyrus. Light microscopic analysis revealed that kainate, but not N-methyl-D-aspartate, induced marked losses of the pyramidal cells in the CAI and CA3 subfields, without affecting the dentate granule cells, for 14 days after administration. Limited proteolysis by V8 protease and supershift, as well as immunoblotting assays using antibodies against c-Fos and c-Jun, invariably gave support for differential expression by N-methyl-D-aspartate and kainate of the activator protein-1 complex consisting of different partner proteins. Moreover, two-dimensional electrophoresis followed by immunoblotting analysis revealed the expression of several nuclear proteins immunoreactive with the anti-c-Fos antibody at molecular weights and isoelectric points clearly different from those of c-Fos itself in response to kainate, but not N-methyl-D-aspartate, in the hippocampus. These results suggest that in vivo N-methyl-D-aspartate signals are predominantly transduced into cell nuclei to express activator protein-1 complex through molecular mechanisms different from those for kainate signals in the granule cells of the dentate gyrus in the murine hippocampus.