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

• Published in: Neuroscience Vol. 93; no. 1; pp. 19 - 31
• Main Authors: Yoneda, Y., Ogita, K., Azuma, Y., Kuramoto, N., Manabe, T., Kitayama, T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01-01-1999
• Subjects: activator protein-1; Animals; c-Fos; c-Jun; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Nucleus - ultrastructure; Cyclic AMP Response Element-Binding Protein - metabolism; Cytoplasmic Granules - drug effects; Cytoplasmic Granules - metabolism; dentate gyrus; Dentate Gyrus - cytology; Dentate Gyrus - drug effects; Dentate Gyrus - metabolism; Dizocilpine Maleate - pharmacology; DNA - metabolism; DNA Probes; Electrophoresis, Polyacrylamide Gel; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Immunoblotting; kainate; Kainic Acid - pharmacology; Kinetics; Male; Mice; N-methyl- d-aspartate; N-Methyl-D-aspartic acid; N-Methylaspartate - pharmacology; Neurons - drug effects; Neurons - metabolism; Neurons - ultrastructure; Proto-Oncogene Proteins c-fos - metabolism; Transcription Factor AP-1 - biosynthesis; Transcription Factor AP-1 - metabolism; EAA, excitatory amino acid; AUC, area under the curve; AP-1, activator protein-1; activator protein-1; N-methyl- d-aspartate; EDTA, ethylenediaminetetra-acetate; Fra, Fos-related antigen; HEPES, N-2-hydroxyethylpiperazine- N′-2-ethanesulfonic acid; MK-801, dizocilpine maleate; c-Fos; SDS, sodium dodecyl sulfate; kainate; CREB, cyclic-AMP response element binding protein; DTT, dithiothreitol; NaGP, sodium β-glycerophosphate; c-Jun; dentate gyrus; PAGE, polyacrylamide gel electrophoresis; EGTA, ethyleneglycolbis(aminoethyl ether)tetra-acetate; NMDA, N-methyl- d-aspartate
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(99)00117-7

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
mg/kg. 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 CA1 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.