Mi Kyoung Seo1, Roger S McIntyre2,3, Hye Yeon Cho1, Chan Hong Lee1, Sung Woo Park1,4, Rodrigo B Mansur2,3, Gyung-Mee Kim5, Jun Hyung Baek5, Young Sup Woo6, Jung Goo Lee7,8,9,10,11, Young Hoon Kim12,13,14,15. 1. Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea. 2. Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, ON, Canada. 3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 4. Department of Health Science and Technology, Graduate School, Inje University, Busan, Republic of Korea. 5. Department of Psychiatry, School of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea. 6. Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 7. Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea. iybihwc@naver.com. 8. Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, ON, Canada. iybihwc@naver.com. 9. Department of Health Science and Technology, Graduate School, Inje University, Busan, Republic of Korea. iybihwc@naver.com. 10. Department of Psychiatry, School of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea. iybihwc@naver.com. 11. Department of Psychiatry, Inje University Haeundae Paik Hospital, 1435, Jwa-dong, Haeundae-gu, Busan, 612-030, Republic of Korea. iybihwc@naver.com. 12. Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea. neuro109@hanmail.net. 13. Department of Health Science and Technology, Graduate School, Inje University, Busan, Republic of Korea. neuro109@hanmail.net. 14. Department of Psychiatry, School of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea. neuro109@hanmail.net. 15. Department of Psychiatry, Inje University Haeundae Paik Hospital, 1435, Jwa-dong, Haeundae-gu, Busan, 612-030, Republic of Korea. neuro109@hanmail.net.
Abstract
RATIONALE: Recent studies have demonstrated that mTORC1 activation may be related to antidepressant action. However, the relationship between mTORC1 signaling activation and currently prescribed antidepressants remains unclear. OBJECTIVE: The aim of the present study was to determine whether alterations in mTORC1 signaling are observable following treatment with tianeptine under toxic conditions induced by B27 deprivation. Additionally, we investigated whether this drug affects synaptic proteins, neurite outgrowth, and spine density via mTORC1 signaling. METHODS: Using Western blotting, we measured the phosphorylation levels of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK in rat primary hippocampal neurons. Changes in BDNF, dendritic outgrowth, spine density, and synaptic proteins (PSD-95, synaptophysin, and GluR1) were measured. RESULTS: Tianeptine significantly increased the phosphorylation of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK. The increase in mTOR phosphorylation was blocked by the PI3K, MEK, and mTORC1 inhibitors. Tianeptine increased BDNF, dendritic outgrowth, spine density, and synaptic proteins; all of these effects were blocked by the mTORC1 inhibitor. CONCLUSIONS: In this study, we demonstrated that tianeptine activates the mTORC1 signaling pathway and increases dendritic outgrowth, spine density, and synaptic proteins through mTORC1 signaling under toxic conditions in rat primary hippocampal neurons.
RATIONALE: Recent studies have demonstrated that mTORC1 activation may be related to antidepressant action. However, the relationship between mTORC1 signaling activation and currently prescribed antidepressants remains unclear. OBJECTIVE: The aim of the present study was to determine whether alterations in mTORC1 signaling are observable following treatment with tianeptine under toxic conditions induced by B27 deprivation. Additionally, we investigated whether this drug affects synaptic proteins, neurite outgrowth, and spine density via mTORC1 signaling. METHODS: Using Western blotting, we measured the phosphorylation levels of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK in rat primary hippocampal neurons. Changes in BDNF, dendritic outgrowth, spine density, and synaptic proteins (PSD-95, synaptophysin, and GluR1) were measured. RESULTS:Tianeptine significantly increased the phosphorylation of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK. The increase in mTOR phosphorylation was blocked by the PI3K, MEK, and mTORC1 inhibitors. Tianeptine increased BDNF, dendritic outgrowth, spine density, and synaptic proteins; all of these effects were blocked by the mTORC1 inhibitor. CONCLUSIONS: In this study, we demonstrated that tianeptine activates the mTORC1 signaling pathway and increases dendritic outgrowth, spine density, and synaptic proteins through mTORC1 signaling under toxic conditions in rat primary hippocampal neurons.
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