Pathophysiological mechanism of mental disorders associated with dysfunction of synaptic release
| Project/Area Number |
17K08324
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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 |
Ohno Yukihiro 大阪薬科大学, 薬学部, 教授 (00432534)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | シナプス分泌 / シナプス小胞タンパク質２A（SV2A) / 精神障害 / 側坐核 / ドパミン遊離 / GABA遊離 / 統合失調症 / ミスセンス変異 / シナプス小胞タンパク質（SV2A） / マイクロダイアリシス / Fosタンパク質発現 / 驚愕反応試験 / プレパルス・インヒビション / 幼若期隔離飼育ストレス / 情動障害 / 攻撃行動 / シナプス小胞蛋白SV2A / 精神疾患 / メタンフェタミン |
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| Outline of Final Research Achievements |
To clarify the influence of synaptic release dysfunction on the onset susceptibility of mental disorders, brain function was analyzed using the rat model carrying a missense mutation in the gene Sv2a encoding synaptic vesicle protein 2A. It was shown that Sv2a mutant rats exhibited hypersensitivity to methamphetamine,impairments of prepulse inhibition in acoustic startle responses, and exaggerated aggressive behaviros induced by juvenile isolation-stress. Sv2a mutant rats also showed neural hyperactivities and enhanced synaptic release of dopamine in the nucleus accumbens. Moreover, the enhanced dopamine release by the Sv2a mutation was found to be due to dysfunction of GABA release from GABA interneurons in the nucleus accumbens.This research provides important information on pathophysiological mechanisms of mental disorders associated with dysfunction of synaptic release.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、神経伝達物質の開口分泌機構の障害が精神疾患の発症脆弱性に大きな影響を及ぼすことが明らかとなった。特に、開口分泌機構を促進的に調節するシナプス小胞タンパク質２A（SV2A)が大脳辺縁系側坐核においてGABAおよびドパミンのシナプス遊離を制御しており、SV2Aの機能障害が統合失調症など精神障害の発症を高める可能性が示唆された。近年、ヒトにおいてもSV2A遺伝子の変異がてんかんや精神障害を誘発することが報告されており、本研究成果はシナプス分泌障害に起因する精神疾患の病態メカニズムに関する重要な情報を提供するもので、その社会的意義は非常に大きいと考えられる。
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Report
(4 results)
Research Products
(35 results)
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[Journal Article] Mechanism Underlying Organophosphate Paraoxon-Induced Kinetic Tremor.2019
Author(s)
Iha HA, Kunisawa N, Shimizu S, Onishi M, Nomura Y, Matsubara N, Iwai C, Ogawa M, Hashimura M, Sato K, Kato M, Ohno Y.
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Journal Title
Neurotox Res.
Volume: 35
Issue: 3
Pages: 575-583
DOI
Related Report
Peer Reviewed
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[Journal Article] Pharmacological characterization of nicotine-induced tremor: Responses to anti-tremor and anti-epileptic agents.2018
Author(s)
N. Kunisawa, S. Shimizu, M. Kato, H. A. Iha, C. Iwai, M. Hashimura, M. Ogawa, S. Kawaji, K. Kawakita, K. Abe, Y. Ohno
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Journal Title
Journal of Pharmacological Sciences
Volume: 137
Issue: 2
Pages: 162-169
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Antiepileptic drugs elevate astrocytic Kir4.1 expression in the rat limbic region.2018
Author(s)
T. Mukai, M. Kinboshi, Y. Nagao, S. Shimizu, A. Ono, Y. Sakagami, A. Okuda, M. Fujimoto, H. Ito, A. Ikeda, Y. Ohno
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Journal Title
Frontiers in Pharmacology
Volume: 9
Pages: 845-845
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Inferior olive is a causative site of the organophosphate paraoxon-induced kinetic tremor2019
Author(s)
Higor Alves Iha, Naofumi Kunisawa, Masaki Kato, Saki Shimizu, Misaki Onishi, Yuji Nomura, Nami Matsubara, Chihiro Iwai, Mizuki Ogawa, Aoi Iwamoto, Rina Machida, Kazuaki Sato, Yukihiro Ohno
Organizer
第46回日本毒性学会学術年会
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