| Project/Area Number |
26460111
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pharmacology in pharmacy
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| Research Institution | Osaka University of Pharmaceutical Sciences |
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Principal Investigator |
Yukihiro Ohno 大阪薬科大学, 薬学部, 教授(移行) (00432534)
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| Co-Investigator(Renkei-kenkyūsha) |
KAWAI YOSHIKO 大阪薬科大学, 薬学部, 講師 (50268299)
SHIMIZU SAKI 大阪薬科大学, 薬学部, 助手 (00630815)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | てんかん / シナプス分泌 / シナプス小胞蛋白SV2A / GABA遊離 / シナプトタグミン１ / てんかん原性 / キンドリング / 神経伝達物質 / GABA / 大脳辺縁系 / シナプス / シナプス小胞タンパク2A （SV2A) / 開口分泌 / グルタミン酸 / シナプス小胞蛋白2A (SV2A) / 動物モデル |
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| Outline of Final Research Achievements |
Synaptic vesicle glycoprotein 2A (SV2A) mediates action potential-dependent neurotransmitter release. To investigate the role of SV2A in regulating epileptogenesis, we generated a novel rat model carrying a Sv2a-targeted missense mutation (L174Q) and analyzed its seizure susceptibilities. The Sv2a mutant rats are highly susceptible to pentylenetetrazole (PTZ) seizure. Kindling with repeated PTZ treatments or amygdala stimulation was also markedly facilitated by the Sv2aL174Q mutation. In vivo microdialysis studies revealed that the Sv2aL174Q mutation reduced depolarization-induced GABA, but not glutamate, release in the limbic regions. Furthermore, the Sv2aL174Q mutation reduced the synaptotagmin1 (Syt1) level. The present results demonstrate that dysfunction of SV2A due to the Sv2aL174Q mutation impairs the synaptic GABA release by reducing the Syt1 level and facilitates the kindling development, illustrating the crucial role of SV2A-GABA system in regulating epileptogenesis.
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