2001 Fiscal Year Final Research Report Summary
Pharmacological research on Ca^<2+> channel abnormality which induces epileptic seizures
| Project/Area Number |
12470018
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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 | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
SASA Masashi Hiroshima University, Faculty of Medicine, Professor, 医学部, 教授 (20025654)
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| Co-Investigator(Kenkyū-buntansha) |
AMANO Taku Hiroshima University, Faculty of Medicine, Research Associate, 医学部, 助手 (10294547)
MATSUBAYASHI Hiroaki Hiroshima University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (60165850)
ISHIHARA Kumatoshi Hiroshima University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (20212912)
SERIKAWA Tadao Kyoto University, Faculty of Medicine, Professor, 医学研究科, 教授 (30025655)
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| Project Period (FY) |
2000 – 2001
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| Keywords | tremor rat / epileptic seizure / aspartoacetylase gene / N-acetyl aspartate / SER / metabotropic glutamate receptor / Ca^<2+> channel / GABA_A receptor |
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| Research Abstract |
The spontaneously epileptic rat (SER : tm/tm, zi/zi) is obtained by mating a heterozygote of the tremor rat (tm/tm) derived from the Kyoto Wistar colony with the zitter rat (zi/zi) from the SD rat clony. The SER shows both absence-like seizures and tonic convulsion after 8 weeks old. We have previously found that tm and zi genes were located on 10q24 and 3q35, respectively.
Based on our studies of 1999-2001, the following results were obtained. (1) Aspartacetylase gene (ASPA) was delated in the tm gene region, resulting in an increase of L-acetyl-aspartate (NAA) in the tremora rat and SER brain. (2) NAA induced an inward current in hippocampal CA3 neurons of normal wister rats via metabotropic glutamate receptors. (3) Application of ASPA recommbinant in adenovirlus into the lateral venticle of the tremor rat resulted in a reduction of epileptic seizures. These findings suggest that increased NAA resulting from ASPA delation is responsible for epiletic seizures in tremora rats and SER. Furthermore, (4) selectively enhanced CA^<2+> inclux was observed in the hippocampal CA3 neurons of SER with single stimulation of the mossy fibers. (5) Vigabatrin, which is an inhibitor of GABA transaminase, acted on the GABA_A receptors of hippocampal CA3 neurons of SER, but not normal wistar rats, to induce a bicucculline-reversible current. These findings confirm the previous findings that SER hippocampal CA3 neurons have abnormaly acting CA^<2+> channels. Inaddigion, changes in GABA_A receptor such as conformation are suggested to be altered in SER hippocampal CA3 neurons.
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