1999 Fiscal Year Final Research Report Summary
Search for proteins associated with schizophrenia in the brain and its therapeutic application
| Project/Area Number |
09557214
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Kanazawa University (1999)
Setsunan University (1997-1998) |
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Principal Investigator |
YONEDA Yukio Kanazawa University, Department of Pharmaceutical Sciences, Professor, 薬学部, 教授 (50094454)
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| Co-Investigator(Kenkyū-buntansha) |
OGITA Kiyokazu Setsunan University, Department of Pharmacology, Lecturer, 薬学部, 講師 (90169219)
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| Project Period (FY) |
1997 – 1999
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| Keywords | Schizophrenia / Negative syndromes / NMDA receptor / Transcription factors / DNA binding activity / Hippocampus / Dentate granule cells / c-Fos protein |
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| Research Abstract |
The present study deals with modulation of gene transcription in the brain, in order to evaluate possible involvement of N-methyl-D-aspartate (NMDA) receptor in mechanisms underlying the crisis of negative syndromes of Schizophrenia. 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 NMDA led to selective and drastic potentiation of DNA binding activity of the transcription factor activator protein-1 (AP1) in murine brain. 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 diminution within 4 h later, which occurred in a manner sensitive to antagonism by an NMDA channel blocker. However, NMDA failed to markedly potentiate AP1 DNA binding in the CA1 and CA3 pyramidal neurons up to 4 h after administration. 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. Moreover, a systemic injection of NMDA resulted in a variety of abnormal behaviors, such as tail biting, in mice for 2 h. These results suggest that modulation of de novo synthesis of particular proteins may underlie mechanisms associated with long-lasting alterations of brain functions such as Schizophrenia.
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