Sustained regulation of neuronal functions through ionotropic glutamate signals

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In this project, we have attempted to demonstrate selective signaling by N-methyl-D-aspartic acid (NMDA) and kainic acid (KA) in vivo in terms of expression of activator protein-1 (AP-1) in nucleus and mitochondria of murine hippocampus. A systemic administration of NMDA resulted in preferential but transient expression of AP-1 in the granule cell layers of the dentate gyrus in the hippocampus, without affecting that in the pyramidal cell layers of CA1 and CA3 subfields. By contrast, KA enhanced DNA binding of AP-1 in adjacent areas around the pyramidal and granule cell layers, in addition to increasing that in neuronal cell layers of the CA1, CA3 and dentate gyrus. Supershift and immunoblot assays invariably gave support for differential expression by NMDA and KA of AP-1 complex consisting of different partner protein. These results suggest that in vivo NMDA signals are predominantly transduced into cell nuclei to express AP-1 complex through molecular mechanisms different from those for KA signals in the granule cells of the dentate gyrus in murine hippocampus.Electrophoretic mobility shift assays revealed that the systemic administration of KA enhanced DNA biding of both AP-1 and cAMP-responsive element binding protein in mitochondria of murine hippocampus. Immunoblot analysis indicated that enhancement of AP-1 DNA binding resulted from expression of c-Fos protein in mitochondria of the hippocampus. These results suggest that KA signals could regulate expression of mitochondrial genes through activation of AP-1.Systemic administration of KA decreased APG-2 level in frontal cortex, hippocampus, and striatum, while HSP70 level was increased in these regions following the administration. NMDA administration did not significantly affect both levels in any of the regions examined. Our results suggest that, unlike the case of HSP70, APG-2 expression could be down regulated by signals peculiar to KA, but not by those peculiar to NMDA, in murine telencephalon.