Abstract
Depression is a complex etiological disease with limited effective treatments. Previous studies have indicated the involvement of miRNAs in the pathophysiology of mood disorders. In this study, we focused on the role and mechanisms of miR-129-5p in depression by successfully constructing mice models of depressive-like behavior via chronic unpredictable mild stress (CUMS) exposure. Herein, miR-129-5p expression was decreased in the hippocampus of CUMS mice model. Upregulation of miR-129-5p reduced depressive-like behaviors of CUMS mice, as revealed in sucrose preference test, novelty suppressed feeding test, forced swim test, tail suspension test, social interaction test. MiR-129-5p upregulation decreased the concentrations and protein levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α), indicating the inhibitory role of miR-129-5p in inflammation. Furthermore, miR-129-5p was identified to target MAPK1. MAPK1 was negatively regulated by miR-129-5p, and silencing of MAPK1 attenuated depressive-like behaviors in CUMS mice. Moreover, MAPK1 downregulation decreased inflammation in the hippocampus of CUMS mice. Upregulation of MAPK1 reversed the suppressive effects of miR-129-5p upregulation on depressive-like behaviors and inflammation in CUMS mice. In conclusion, the current study identified that miR-129-5p reduces depressive-like behaviors and suppresses inflammation by targeting MAPK1 in CUMS mice, offering a novel molecular interpretation for depression prevention.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Calabro M et al (2019) Genes Involved in Neurodevelopment, Neuroplasticity and Major Depression: No Association for CACNA1C, CHRNA7 and MAPK1. Clin Psychopharmacol Neurosci 17:364–368. https://doi.org/10.9758/cpn.2019.17.3.364
Calati R et al (2013) Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients. Prog Neuro-Psychopharmacol Biol Psychiatr 44:271–278. https://doi.org/10.1016/j.pnpbp.2013.03.005
Chen YH et al (2015) Quetiapine and repetitive transcranial magnetic stimulation ameliorate depression-like behaviors and up-regulate the proliferation of hippocampal-derived neural stem cells in a rat model of depression: the involvement of the BDNF/ERK signal pathway. Pharmacol Biochem Behav 136:39–46. https://doi.org/10.1016/j.pbb.2015.07.005
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim E, Lanctôt KJBp (2010) A meta-analysis of cytokines in major depression. Biol Psychiatr 67:446–457. https://doi.org/10.1016/j.biopsych.2009.09.033
Dwivedi Y, Rizavi HS, Conley RR, Pandey GN (2006) ERK MAP kinase signaling in post mortem brain of suicide subjects differential regulation of upstream Raf kinases Raf 1 and B Raf. Mol Psychiatr 11:86–98. https://doi.org/10.1038/sj.mp.4001744
Dwivedi Y, Rizavi HS, Roberts RC, Conley RC, Tamminga CA, Pandey GN (2001) Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J Neurochem 77:916–928. https://doi.org/10.1046/j.1471-4159.2001.00300.x
Dwivedi Y, Rizavi HS, Zhang H, Roberts RC, Conley RR, Pandey GN (2009) Aberrant extracellular signal-regulated kinase (ERK)1/2 signalling in suicide brain: role of ERK kinase 1 (MEK1). Int Journal Neuropsychopharmacol 12:1337–1354. https://doi.org/10.1017/s1461145709990575
DwivediEoott YJ (2017) microRNA-124: a putative therapeutic target and biomarker for major depression. Expert Opin Ther Targets 21:653–656. https://doi.org/10.1080/14728222.2017.1328501
Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114. https://doi.org/10.1038/nrg2290
First M, Gil-Ad I, Taler M, Tarasenko I, Novak N, Weizman A (2011) The effects of fluoxetine treatment in a chronic mild stress rat model on depression-related behavior, brain neurotrophins and ERK expression. J Mol Neurosci. https://doi.org/10.1007/s12031-011-9515-5
Geng Z, Xu F, Zhang Y (2016) MiR-129-5p-mediated Beclin-1 suppression inhibits endothelial cell autophagy in atherosclerosis. Am J Trans Res 8(4):1886–1894
Gourley SL, Wu FJ, Kiraly DD, Ploski JE, Kedves AT, Duman RS, Taylor JR (2008) Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiat 63:353–359. https://doi.org/10.1016/j.biopsych.2007.07.016
Guan YJ et al (2018) Evidence that miR-146a attenuates aging- and trauma-induced osteoarthritis by inhibiting Notch 1, IL-6, and IL-1 mediated catabolism. Aging Cell. https://doi.org/10.1111/acel.12752
Hannon TS, Rofey DL, Lee S, Arslanian SA (2013) Depressive symptoms and metabolic markers of risk for type 2 diabetes in obese adolescents. Pediatr Diabetes 14:497–503. https://doi.org/10.1111/pedi.12035
Herder C, Hermanns NJSii, (2019) Subclinical inflammation and depressive symptoms in patients with type 1 and type 2 diabetes. Sem Immunopathol 41:477–489. https://doi.org/10.1007/s00281-019-00730-x
Jo WK, Zhang Y, Emrich HM, Dietrich DE (2015) Glia in the cytokine-mediated onset of depression: fine tuning the immune response. Front Cell Neurosci 9:268. https://doi.org/10.3389/fncel.2015.00268
Köhler O, Benros M (2015) Krogh JJJp anti-inflammatory intervention in depression-reply. JAMA Psychiatr 72:512–513. https://doi.org/10.1001/jamapsychiatry.2014.3186
Kopschina Feltes P, Doorduin J, Klein HC, Juarez-Orozco LE, Dierckx RA, Moriguchi-Jeckel CM, de Vries EF (2017) Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy. J Psychopharmacol 31:1149–1165. https://doi.org/10.1177/0269881117711708
Lian N, Niu Q, Lei Y, Li X, Li Y, Song XJCc, (2018) MiR-221 is involved in depression by regulating Wnt2/CREB/BDNF axis in hippocampal neurons. Cell Cycle. https://doi.org/10.1080/15384101.2018.1556060
M H, et al (2019) Sensory profiles and immune-related expression patterns of patients with and without neuropathic pain after peripheral nerve lesion. Pain 160:2316–2327. https://doi.org/10.1097/j.pain.0000000000001623
ME L, et al (2020) Depression and psychosocial stress are associated with subclinical carotid atherosclerosis among women living with HIV. J Am Heart Assoc. https://doi.org/10.1161/jaha.120.016425
Miller A, Maletic V (2009) Raison CJBp inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatr 65:732–741. https://doi.org/10.1016/j.biopsych.2008.11.029
O’Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG (2007) Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res 41:326–331. https://doi.org/10.1016/j.jpsychires.2006.05.013
Peng H, Wang HB, Wang L, Zhou B, Li XY, Tan J (2018) Gsk3beta aggravates the depression symptoms in chronic stress mouse model. J Int Neurosci 17:169–175. https://doi.org/10.31083/jin-170050
Qi X, Lin W, Li J, Li H, Wang W, Wang D, Sun M (2008) Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol Dis 31:278–285. https://doi.org/10.1016/j.nbd.2008.05.003
Raison C, Capuron L (2006) Miller AJTii cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27:24–31. https://doi.org/10.1016/j.it.2005.11.006
Rihmer Z, Gonda X (2011) Antidepressant-resistant depression and antidepressant-associated suicidal behaviour: the role of underlying bipolarity. Depress Res Treat. https://doi.org/10.1155/2011/906462
Schatzberg AF (2015) Development of new psychopharmacological agents for depression and anxiety. Psychiatr Clin North Am 38:379–393. https://doi.org/10.1016/j.psc.2015.05.009
Schillani G, Era D, Cristante T, Mustacchi G, Richiardi M, Grassi L, Giraldi T (2012) 5-HTTLPR polymorphism and anxious preoccupation in early breast cancer patients. Radiol Oncol 46:321–327. https://doi.org/10.2478/v10019-012-0024-0
Song A et al (2020) NLRP1 inflammasome contributes to chronic stress-induced depressive-like behaviors in mice. J Neuroinflam 17:178. https://doi.org/10.1186/s12974-020-01848-8
Song MF et al (2015) CSF miR-16 is decreased in major depression patients and its neutralization in rats induces depression-like behaviors via a serotonin transmitter system. J Affect Disord 178:25–31. https://doi.org/10.1016/j.jad.2015.02.022
Song Q, Fan C, Wang P, Li Y, Yang M, Yu SJJon, (2018) Hippocampal CA1 βCaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression. J Neuroinflam. https://doi.org/10.1186/s12974-018-1377-0
Surget A et al (2009) Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal Neuropsychopharmacology : official publication of the American College of. Neuropsychopharmacology 34:1363–1380. https://doi.org/10.1038/npp.2008.76
Tang CZ, Zhang DF, Yang JT, Liu QH, Wang YR, Wang WS (2019) Overexpression of microRNA-301b accelerates hippocampal microglia activation and cognitive impairment in mice with depressive-like behavior through the NF-kappaB signaling pathway. Cell Death Dis. https://doi.org/10.1038/s41419-019-1522-4
Taylor DJ, Walters HM, Vittengl JR, Krebaum S, Jarrett RB (2010) Which depressive symptoms remain after response to cognitive therapy of depression and predict relapse and recurrence? J Affect Disord 123:181–187. https://doi.org/10.1016/j.jad.2009.08.007
Tian J, Song T, Wang W, Wang H, Zhang Z (2019) miR-129–5p alleviates neuropathic pain through regulating HMGB1 expression in CCI rat models. J Mol Neurosci MN. https://doi.org/10.1007/s12031-019-01403-y
Wan Y, Yang ZJCc, (2020) LncRNA NEAT1 affects inflammatory response by targeting miR-129-5p and regulating Notch signaling pathway in epilepsy. Cell Cycle. https://doi.org/10.1080/15384101.2020.1711578
Wang P et al (2016) Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray. Proceed Natl Acad Sci USA. https://doi.org/10.1073/pnas.1609198113
Wang Y, Li W, Wu Y, Yin Y, Dong L, Chen Z, Wu WJJon, (2015) Acid-sensing ion channel 1a contributes to the effect of extracellular acidosis on NLRP1 inflammasome activation in cortical neurons. J Neuroinflam. https://doi.org/10.1186/s12974-015-0465-7
Wuwongse S et al (2013) Effects of corticosterone and amyloid-beta on proteins essential for synaptic function: implications for depression and Alzheimer’s disease. Biochem Biophys Acta 1832:2245–2256. https://doi.org/10.1016/j.bbadis.2013.07.022
Yang J et al (2019) Extracellular vesicle lncRNA metastasis-associated lung adenocarcinoma transcript 1 released from glioma stem cells modulates the inflammatory response of microglia after lipopolysaccharide stimulation through regulating miR-129-5p/High Mobility Group Box-1 Protein Axis. Front Immunol 10:3161. https://doi.org/10.3389/fimmu.2019.03161
Zhang L, Liao Y, Tang L (2019) MicroRNA-34 family: a potential tumor suppressor and therapeutic candidate in cancer. J Exp Clin Cancer Res. https://doi.org/10.1186/s13046-019-1059-5
Zhang X et al (2018) The role of miR-29c/B7-H3 axis in children with allergic asthma. J Trans Med. https://doi.org/10.1186/s12967-018-1590-8
Acknowledgements
Not applicable
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
No potential conflict of interest was reported by the author(s).
Additional information
Communicated by Sreedharan Sajikumar.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Chang, J., Zhang, Y., Shen, N. et al. MiR-129-5p prevents depressive-like behaviors by targeting MAPK1 to suppress inflammation. Exp Brain Res 239, 3359–3370 (2021). https://doi.org/10.1007/s00221-021-06203-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-021-06203-8