Sirtuin 6 (SIRT6) has been reported to play a key role in cognitive function and mood regulation, yet its role in mood disorders is not completely understood. Here, we confirmed that knockdown of hippocampal SIRT6 alleviated depression-like behaviors induced by chronic unpredictable stress (CUS) in mice. Our in vitro data showed that SIRT6 negatively regulated protein kinase B (AKT) signaling by deacetylating histone 3 at Lys9 and Lys56. Knockdown of SIRT6 significantly increased AKT phosphorylation activity, while decreased collapsin response mediator protein 2 (CRMP2) phosphorylation activity. Furthermore, pharmacologic inhibition of SIRT6 by ferulic acid (FA) (40 or 80 mg· kg−1 per day, i.g.) could activate AKT/CRMP2 pathway in vitro, which has been proved to exert an antidepressant-like effect on CUS-induced depressive models. In conclusion, our study suggested that hippocampal SIRT6 contributes to the performance of depression-like behaviors by suppressing AKT/CRMP2 signaling, and FA ameliorates CUS-induced depression-like behaviors in mice as a potential pharmacologic inhibitor of SIRT6.
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Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894–902.
Nasca C, Bigio B, Zelli D, Nicoletti F, McEwen BS. Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility. Mol Psychiatry. 2015;20:755–63.
Duman RS. Neurobiology of stress, depression, and rapid acting antidepressants: remodeling synaptic connections. Depress Anxiety. 2014;31:291–6.
Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338:68–72.
Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25:138–45.
Alageel A, Tomasi J, Tersigni C, Brietzke E, Zuckerman H, Subramaniapillai M, et al. Evidence supporting a mechanistic role of sirtuins in mood and metabolic disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2018;86:95–101.
Lo Iacono L, Visco-Comandini F, Valzania A, Viscomi MT, Coviello M, Giampà A, et al. Adversity in childhood and depression: linked through SIRT1. Transl Psychiatry. 2015;5:e629.
Abe N, Uchida S, Otsuki K, Hobara T, Yamagata H, Higuchi F, et al. Altered sirtuin deacetylase gene expression in patients with a mood disorder. J Psychiatr Res. 2011;45:1106–12.
Abe-Higuchi N, Uchida S, Yamagata H, Higuchi F, Hobara T, Hara K, et al. Hippocampal sirtuin 1 signaling mediates depression-like behavior. Biol Psychiatry. 2016;80:815–26.
Libert S, Pointer K, Bell EL, Das A, Cohen DE, Asara JM, et al. SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell. 2011;147:1459–72.
Zhang Z, Zhang P, Qi GJ, Jiao FJ, Wang QZ, Yan JG, et al. CDK5-mediated phosphorylation of Sirt2 contributes to depression-like behavior induced by social defeat stress. Biochim Biophys Acta Mol Basis Dis. 2018;1864:533–41.
Muñoz-Cobo I, Belloch FB, Díaz-Perdigón T, Puerta E, Tordera RM. SIRT2 inhibition reverses anhedonia in the Vglut1+/− depression model. Behav Brain Res. 2017;335:128–31.
Liu R, Dang W, Du Y, Zhou Q, Jiao K, Liu Z. SIRT2 is involved in the modulation of depressive behaviors. Sci Rep. 2015;5:8415.
Li W, Zhu Y, Liu X, Hou J, Fang J, Shen JX, et al. Phencynonate mediates antidepressant response by activating sirtuin 6-SOD2/Prdx6 pathway. Biochem Biophys Res Commun. 2018;505:898–904.
Mao Q, Gong X, Zhou C, Tu Z, Zhao L, Wang L, et al. Up-regulation of SIRT6 in the hippocampus induced rats with depression-like behavior via the block Akt/GSK3b signaling pathway. Behav Brain Res. 2017;323:38–46.
Hers I, Vincent EE, Tavare JM. Akt signalling in health and disease. Cell Signal. 2011;23:1515–27.
Leibrock C, Ackermann TF, Hierlmeier M, Lang F, Borgwardt S, Lang UE. Akt2 deficiency is associated with anxiety and depressive behavior in mice. Cell Physiol Biochem. 2013;32:766–77.
Papazoglou IK, Jean A, Gertler A, Taouis M, Vacher CM. Hippocampal GSK3β as a molecular link between obesity and depression. Mol Neurobiol. 2015;52:363–74.
Ackermann TF, Kempe DS, Lang F, Lang UE. Hyperactivity and enhanced curiosity of mice expressing PKB/SGK-resistant glycogen synthase kinase-3 (GSK-3). Cell Physiol Biochem. 2010;25:775–86.
Qiao J, Rong L, Wang Z, Zhang M. Involvement of Akt/GSK3β/CREB signaling pathway on chronic omethoate induced depression-like behavior and improvement effects of combined lithium chloride and astaxanthin treatment. Neurosci Lett. 2017;649:55–61.
Quach TT, Honnorat J, Kolattukudy PE, Khanna R, Duchemin AM. CRMPs: critical molecules for neurite morphogenesis and neuropsychiatric diseases. Mol Psychiatry. 2015;20:1037–45.
Zhang H, Kang E, Wang Y, Yang C, Yu H, Wang Q, et al. Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice. Nat Commun. 2018;9:16229.
Nada SE, Tulsulkar J, Raghavan A, Hensley K, Shah ZA. A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia. Neurochem Int. 2012;61:1357–63.
Wilson SM, Ki Yeon S, Yang XF, Park KD, Khanna R. Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3β and CDK5 following traumatic brain injury. Front Cell Neurosci. 2014;8:135.
Yang Z, Kuboyama T, Tohda C. A systematic strategy for discovering a therapeutic drug for Alzheimer’s disease and its target molecule. Front Pharmacol. 2017;8:340.
Ip JP, Fu AK, Ip NY. CRMP2: functional roles in neural development and therapeutic potential in neurological diseases. Neuroscientist. 2014;20:589–98.
Hensley K, Kursula P. Collapsin response mediator protein-2 (CRMP2) is a plausible etiological factor and potential therapeutic target in Alzheimer’s disease: comparison and contrast with microtubule-associated protein Tau. J Alzheimers Dis. 2016;53:1–14.
Nakamura H, Yamashita N, Kimura A, Kimura Y, Hirano H, Makihara H, et al. Comprehensive behavioral study and proteomic analyses of CRMP2-deficient mice. Genes Cells. 2016;21:1059–79.
Zhang JN, Koch JC. Collapsin response mediator protein-2 plays a major protective role in acute axonal degeneration. Neural Regen Res. 2017;12:692–5.
Saitoh F, Hagiwara H, Wakatsuki S, Araki T. Carboxymethylation of CRMP2 is associated with decreased Schwann cell myelination efficiency. Neurosci Res. 2018;18:30492–94.
Zhang JN, Michel U, Lenz C, Friedel CC, Köster S, d’Hedouville Z, et al. Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration. Sci Rep. 2016;6:37050.
Dustrude ET, Wilson SM, Ju W, Xiao Y, Khanna R. CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking. J Biol Chem. 2013;288:24316–31.
Moutal A, Dustrude ET, Largent-Milnes TM, Vanderah TW, Khanna M, Khanna R. Blocking CRMP2 SUMOylation reverses neuropathic pain. Mol Psychiatry. 2018;23:2119–21.
Liu Y, Lin D, Liu C, Zhao Y, Shen Z, Zhang K, et al. Cyclin-dependent kinase 5/Collapsin response mediator protein 2 pathway may mediate sevoflurane-induced dendritic development abnormalities in rat cortical neurons. Neurosci Lett. 2017;651:21–9.
Nagai J, Owada K, Kitamura Y, Goshima Y, Ohshima T. Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses. Exp Neurol. 2016;277:283–95.
Cole AR, Soutar MP, Rembutsu M, van Aalten L, Hastie CJ, McLauchlan H, et al. Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation. J Biol Chem. 2008;283:18227–37.
Zheng X, Cheng Y, Chen Y, Yue Y, Li Y, Xia S, et al. Ferulic acid improves depressive-like behavior in prenatally-stressed offspring rats via anti-inflammatory activity and HPA axis. Int J Mol Sci. 2019;20:E493.
Zheng D, Sabbagh JJ, Blair LJ, Darling AL, Wen X, Dickey CA. MicroRNA-511 binds to FKBP5 mRNA, which encodes a chaperone protein, and regulates neuronal differentiation. J Biol Chem. 2016;291:17897–906.
Higuchi F, Uchida S, Yamagata H, Abe-Higuchi N, Hobara T, Hara K, et al. Hippocampal microRNA-124 enhances chronic stress resilience in mice. J Neurosci. 2016;36:7253–67.
Dif N, Euthine V, Gonnet E, Laville M, Vidal H, Lefai E. Insulin activates human sterol-regulatory-element-binding protein-1c (SREBP-1c) promoter through SRE motifs. Biochem J. 2006;400:179–88.
Sundaresan NR, Vasudevan P, Zhong L, Kim G, Samant S, Parekh V, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med. 2012;18:1643–50.
Pan H, Guan D, Liu X, Li J, Wang L, Wu J, et al. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res. 2016;26:190–205.
Wu Z, Wang G, Wei Y, Xiao L, Wang H. PI3K/AKT/GSK3β/CRMP-2-mediated neuroplasticity in depression induced by stress. Neuroreport. 2018;29:1256–63.
Liu YM, Hu CY, Shen JD, Wu SH, Li YC, Yi LT. Elevation of synaptic protein is associated with the antidepressant-like effects of ferulic acid in a chronic model of depression. Physiol Behav. 2017;169:184–8.
Zeni ALB, Camargo A, Dalmagro AP. Ferulic acid reverses depression-like behavior and oxidative stress induced by chronic corticosterone treatment in mice. Steroids. 2017;125:131–6.
Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012;483:218–21.
Zhang W, Wan H, Feng G, Qu J, Wang J, Jing Y, et al. SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature. 2018;560:661–5.
Ludka FK, Constantino LC, Dal-Cim T, Binder LB, Zomkowski A, Rodrigues AL, et al. Involvement of PI3K/Akt/GSK-3b and mTOR in the antidepressant-like effect of atorvastatin in mice. J Psychiatr Res. 2016;82:50–57.
Cunha MP, Budni J, Ludka FK, Pazini FL, Rosa JM, Oliveira Á, et al. Involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. Mol Neurobiol. 2016;53:2954–68.
Shao J, Yang X, Liu T, Zhang T, Xie QR, Xia W. Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage. Protein Cell. 2016;7:281–90.
Pillai VB, Sundaresan NR, Gupta MP. Regulation of Akt signaling by sirtuins its implication in cardiac hypertrophy and aging. Circ Res. 2014;114:368–78.
Wakatsuki S, Saitoh F, Araki T. ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat Cell Biol. 2011;13:1415–23.
Kumar N, Pruthi V. Potential applications of ferulic acid from natural sources. Biotechnol Rep. 2014;4:86–93.
Chen J, Lin D, Zhang C, Li G, Zhang N, Ruan L, et al. Antidepressant-like effects of ferulic acid: involvement of serotonergic and norepinergic systems. Metab Brain Dis. 2015;30:129–36.
Song MT, Ruan J, Zhang RY, Deng J, Ma ZQ, Ma SP. Astragaloside IV ameliorates neuroinflammationinduced depressive-like behaviors in mice via the PPARγ/NF-κB/NLRP3 inflammasome axis. Acta Pharmacol Sin. 2018;39:1559–70.
Solanki N, Salvi A, Patki G, Salim S. Modulating oxidative stress relieves stress-induced behavioral and cognitive impairments in rats. Int J Neuropsychopharmacol. 2017;20:550–61.
We thank Prof. Yi Yang, Ningxia Medical University, for providing antibodies (anti-AKT and anti-phospho-AKT). In addition, we thank Prof. Li-jun Zhao, Shaanxi Normal University, for gifting HT-22 cells. This study was also supported by Fundamental Research Fund for the Central Universities (GK202003054) and Natural Science Basic Research Plan in Shaanxi Province of China (No. 2019JM-285).
The authors declare no competing interests.
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Li, W., Liu, X. & Qiao, H. Downregulation of hippocampal SIRT6 activates AKT/CRMP2 signaling and ameliorates chronic stress-induced depression-like behavior in mice. Acta Pharmacol Sin 41, 1557–1567 (2020). https://doi.org/10.1038/s41401-020-0387-5
- chronic unpredictable stress
- depression-like behaviors
Medicinal Research Reviews (2021)
Frontiers in Cell and Developmental Biology (2020)