SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling
Abstract Impaired neuroplasticity is a one of the key pathological mechanism of depression. Sirtuin 1 plays a crucial role in neuroplasticity; however, its precise mechanisms remain unclear. This study examined whether sirtuin 1 regulates dendritic outgrowth and spine formation via mTORC1 signaling...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-06203-6 |
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| author | Mi Kyoung Seo Jung Goo Lee Ji Hyun Kim Dae-Hyun Seog Sehoon Jeong Seong-Ho Kim Jin Young Lee Sung Woo Park |
| author_facet | Mi Kyoung Seo Jung Goo Lee Ji Hyun Kim Dae-Hyun Seog Sehoon Jeong Seong-Ho Kim Jin Young Lee Sung Woo Park |
| author_sort | Mi Kyoung Seo |
| collection | DOAJ |
| description | Abstract Impaired neuroplasticity is a one of the key pathological mechanism of depression. Sirtuin 1 plays a crucial role in neuroplasticity; however, its precise mechanisms remain unclear. This study examined whether sirtuin 1 regulates dendritic outgrowth and spine formation via mTORC1 signaling in rat primary cortical cells under dexamethasone-induced neurotoxic conditions. Cortical cells were treated with SRT2104 (0.1, 1, and 10 µM), a selective sirtuin 1 activator, in the presence of dexamethasone (500 µM). Protein levels of sirtuin 1, mTORC1 signaling components, and synaptic markers (PSD-95 and GluA1) were analyzed by Western blotting, while dendritic outgrowth and spine density were assessed via immunofluorescence. SRT2104 significantly increased sirtuin 1 expression and ERK1/2 (a downstream target of sirtuin 1) phosphorylation. SRT2104 led to a substantial augmentation in the phosphorylation levels of mTORC1, as well as 4E-BP1 and p70S6K, which are downstream targets of mTORC1. Furthermore, SRT2104 led to an increase in dendritic outgrowth and spine density. Conversely, sirtuin 1 knockdown by siRNA transfection markedly reduced ERK1/2 and mTORC1 phosphorylation, as well as dendritic complexity and spine formation. These results suggest that sirtuin 1 promotes neuroplasticity by activating mTORC1 signaling, providing potential therapeutic implications for depression treatment. |
| format | Article |
| id | doaj-art-6e633e42b6b940fdbed6d56befa53a89 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-6e633e42b6b940fdbed6d56befa53a892025-08-20T03:03:24ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-06203-6SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signalingMi Kyoung Seo0Jung Goo Lee1Ji Hyun Kim2Dae-Hyun Seog3Sehoon Jeong4Seong-Ho Kim5Jin Young Lee6Sung Woo Park7Department of Convergence Biomedical Science, College of Medicine, Inje UniversityPaik Institute for Clinical Research, Inje UniversityPaik Institute for Clinical Research, Inje UniversityDepartment of Convergence Biomedical Science, College of Medicine, Inje UniversityDepartment of Artificial Intelligence and Data Science, Sejong UniversityPaik Institute for Clinical Research, Inje UniversityDepartment of Pharmacy, Kyungsung UniversityDepartment of Convergence Biomedical Science, College of Medicine, Inje UniversityAbstract Impaired neuroplasticity is a one of the key pathological mechanism of depression. Sirtuin 1 plays a crucial role in neuroplasticity; however, its precise mechanisms remain unclear. This study examined whether sirtuin 1 regulates dendritic outgrowth and spine formation via mTORC1 signaling in rat primary cortical cells under dexamethasone-induced neurotoxic conditions. Cortical cells were treated with SRT2104 (0.1, 1, and 10 µM), a selective sirtuin 1 activator, in the presence of dexamethasone (500 µM). Protein levels of sirtuin 1, mTORC1 signaling components, and synaptic markers (PSD-95 and GluA1) were analyzed by Western blotting, while dendritic outgrowth and spine density were assessed via immunofluorescence. SRT2104 significantly increased sirtuin 1 expression and ERK1/2 (a downstream target of sirtuin 1) phosphorylation. SRT2104 led to a substantial augmentation in the phosphorylation levels of mTORC1, as well as 4E-BP1 and p70S6K, which are downstream targets of mTORC1. Furthermore, SRT2104 led to an increase in dendritic outgrowth and spine density. Conversely, sirtuin 1 knockdown by siRNA transfection markedly reduced ERK1/2 and mTORC1 phosphorylation, as well as dendritic complexity and spine formation. These results suggest that sirtuin 1 promotes neuroplasticity by activating mTORC1 signaling, providing potential therapeutic implications for depression treatment.https://doi.org/10.1038/s41598-025-06203-6DepressionDexamethasonemTORC1 signalingNeuroplasticitySirtuin 1SRT2104 |
| spellingShingle | Mi Kyoung Seo Jung Goo Lee Ji Hyun Kim Dae-Hyun Seog Sehoon Jeong Seong-Ho Kim Jin Young Lee Sung Woo Park SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling Scientific Reports Depression Dexamethasone mTORC1 signaling Neuroplasticity Sirtuin 1 SRT2104 |
| title | SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling |
| title_full | SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling |
| title_fullStr | SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling |
| title_full_unstemmed | SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling |
| title_short | SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling |
| title_sort | srt2104 enhances dendritic outgrowth and spine formation through sirtuin 1 mediated mtorc1 signaling |
| topic | Depression Dexamethasone mTORC1 signaling Neuroplasticity Sirtuin 1 SRT2104 |
| url | https://doi.org/10.1038/s41598-025-06203-6 |
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