Pathophysiological impact of diverse deregulation of tonic inhibition in Angelman syndrome
| Project/Area Number |
18H02777
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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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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
Egawa Kiyoshi 北海道大学, 医学研究院, 助教 (40450829)
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| Co-Investigator(Kenkyū-buntansha) |
岡野 栄之 慶應義塾大学, 医学部(信濃町), 教授 (60160694)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
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| Keywords | アンジェルマン症候群 / GABA / GABA持続抑制 / GABA作動性持続抑制 / GABA作動性抑制 / 遺伝性てんかん / 精神運動発達遅滞 / 発達障害 / GABA抑制 / 自閉症スペクトラム |
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| Outline of Final Research Achievements |
We investigated tonic inhibition of cortical pyramidal neuron and thalamic relay neurons in AS mice. Tonic inhibition was decreased in the hippocampus and the cortex, but not in thalamo-cortical relay neurons. AS mice showed significantly higherδ-θwave power in intracranial EEG. This epileptic feature was improved by MP-Ⅲ-22, positive allosteric modulator forα5 subunit-containing GABAa receptors. By using iPS cells-derived neurons, we also discovered that intrinsic firing property is maintained in AS interneurons but intracellular Cl- regulating protein was dysregulated in AS model mice. These results suggest that not a global but a relative decrease in tonic inhibition in the cortex/hippocampus can disturb the regular thalamo-cortical networks, resulting in epilepsy of AS. Our findings can contribute to the deeper understanding of pathophysiology of AS and developing a new therapeutic strategy.
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| Academic Significance and Societal Importance of the Research Achievements |
今回の研究により、アンジェルマン症候群（AS)における皮質神経細胞選択的なシナプス外持続抑制の減弱がその病態生理に重要であることを明らかにした。GABA作動性抑制は薬剤により調整可能であり、α5サブユニット選択的陽性変力薬がてんかんの治療に有効である可能性が示唆された。持続抑制が全体に下がっているのではなく、領域間の不均等により症状が発生しうる、という結果はこれまで全く報告されておらず、ASのみならず中枢神経疾患全体への病態生理探索に一石を投じるものと思われる。また、クロライドトランスポーターの調整薬であるブメタニドも知的障害の改善に寄与することが示された。将来的な治療への応用が期待される。
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Report
(4 results)
Research Products
(14 results)
