Abstract
Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression. Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in blood, as compared with control or resilient groups. We show further that upregulation and downregulation of miR-218 levels specifically in the mPFC correlate with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility vs. resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.
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References
Roy B, Dwivedi Y. miRNAs as critical epigenetic players in determining neurobiological correlates of major depressive disorder. In: Kim Y-K, editor. Understanding depression: Vol. 1. Biomedical and neurobiological background. Singapore: Springer Singapore; 2018. pp. 51–69.
Tavakolizadeh J, Roshanaei K, Salmaninejad A, Yari R, Nahand JS, Sarkarizi HK, et al. MicroRNAs and exosomes in depression: potential diagnostic biomarkers. J Cell Biochem. 2018;119:3783–3797.
Dias C, Feng J, Sun H, Shao N-y, Mazei-Robison MS, Damez-Werno D, et al. β-catenin mediates behavioral resilience through Dicer1/microRNA regulation. Nature. 2014;516:51–55.
Lopez JP, Lim R, Cruceanu C, Crapper L, Fasano C, Labonte B, et al. miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nat Med. 2014;20:764–8.
Issler O, Haramati S, Paul Evan D, Maeno H, Navon I, Zwang R, et al. MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron. 2014;83:344–60.
Roy B, Dunbar M, Shelton RC, Dwivedi Y. Identification of microRNA-124-3p as a putative epigenetic signature of major depressive disorder. Neuropsychopharmacology. 2017;42:864–75.
Torres-Berrío A, Lopez JP, Bagot RC, Nouel D, Dal Bo G, Cuesta S, et al. DCC confers susceptibility to depression-like behaviors in humans and mice and is regulated by miR-218. Biol Psychiatry. 2017;81:306–15.
Geaghan M, Cairns MJ. MicroRNA and posttranscriptional dysregulation in psychiatry. Biol Psychiatry. 2015;78:231–9.
Smalheiser NR, Lugli G, Rizavi HS, Torvik VI, Turecki G, Dwivedi Y. MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS ONE. 2012;7:e33201.
Lopez JP, Fiori LM, Gross JA, Labonte B, Yerko V, Mechawar N, et al. Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers. Int J Neuropsychopharmacol. 2014;17:23–32.
Deng Z-F, Zheng H-L, Chen J-G, Luo Y, Xu J-F, Zhao G, et al. miR-214-3p targets β-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice. Cerebral Cortex. 2018;29:1509–19.
Roy B, Wang Q, Palkovits M, Faludi G, Dwivedi Y. Altered miRNA expression network in locus coeruleus of depressed suicide subjects. Sci Reports. 2017;7:4387.
Dwivedi Y, Roy B, Lugli G, Rizavi H, Zhang H, Smalheiser NR. Chronic corticosterone-mediated dysregulation of microRNA network in prefrontal cortex of rats: relevance to depression pathophysiology. Transl Psychiatry. 2015;5:e682.
Akil H, Gordon J, Hen R, Javitch J, Mayberg H, McEwen B, et al. Treatment resistant depression: a multi-scale, systems biology approach. Neurosci Biobehav Rev. 2018;84:272–88.
Belzeaux R, Lin R, Turecki G. Potential use of microRNA for monitoring therapeutic response to antidepressants. CNS Drugs. 2017;31:253–62.
Rao P, Benito E, Fischer A. MicroRNAs as biomarkers for CNS disease. Front Mol Neurosci. 2013;6:39.
Lopez JP, Fiori LM, Cruceanu C, Lin R, Labonte B, Cates HM. et al. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes. Nat Commun. 2017;8:15497.
Fan H-m, Sun X-y, Guo W, Zhong A-f, Niu W, Zhao L, et al. Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients. J Psych Res. 2014;59:45–52.
Belzeaux R, Bergon A, Jeanjean V, Loriod B, Formisano-Tréziny C, Verrier L, et al. Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode. Transl Psychiatry. 2012;2:e185.
Krishnan V, Han M-H, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.
Golden SA, Covington HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protocols. 2011;6:1183–91.
Manitt C, Eng C, Pokinko M, Ryan RT, Torres-Berrio A, Lopez JP, et al. dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients. Transl Psychiatry. 2013;3:e338.
Mendes-Silva AP, Diniz BS, Tolentino Araújo GT, de Souza Nicolau E, Pereira KS, Silva Ferreira CM, et al. MiRNAs and their role in the correlation between major depressive disorder, mild cognitive impairment and Alzheimer’s disease. J Alzheimer’s Association. 2017;13:P1017–P1018.
Razzoli M, Carboni L, Andreoli M, Ballottari A, Arban R. Different susceptibility to social defeat stress of BalbC and C57BL6/J mice. Behav Brain Res. 2011;216:100–8.
Jimenez-Mateos EM, Engel T, Merino-Serrais P, McKiernan RC, Tanaka K, Mouri G, et al. Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med. 2012;18:1087–94.
Cuesta S, Restrepo-Lozano JM, Silvestrin S, Nouel D, Torres-Berrío A, Reynolds LM, et al. Non-contingent exposure to amphetamine in adolescence recruits miR-218 to regulate Dcc expression in the VTA. Neuropsychopharmacology. 2017;43:900–11.
Hanson LR, Fine JM, Svitak AL, Faltesek KA. Intranasal administration of CNS therapeutics to awake mice. JoVE. 2013;74:e4440.
Paxinos G, Franklin K. Paxinos and Franklin’s the mouse brain in stereotaxic coordinates. Boston, Amsterdam: Elsevier/Academic Press; 2013.
Campbell MJ, Morrison JH. Monoclonal antibody to neurofilament protein (SMI-32) labels a subpopulation of pyramidal neurons in the human and monkey neocortex. J Comp Neurol. 1989;282:191–205.
Voelker CCJ, Garin N, Taylor JSH, Gähwiler BH, Hornung J-P, Molnár Z. Selective neurofilament (SMI-32, FNP-7 and N200) expression in subpopulations of layer V pyramidal neurons in vivo and in vitro. Cerebral Cortex. 2004;14:1276–86.
Sternberger LA, Sternberger NH. Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ. Proc Natl Acad Sci USA. 1983;80:6126–30.
Hof PR, Morrison JH. Neurofilament protein defines regional patterns of cortical organization in the macaque monkey visual system: a quantitative immunohistochemical analysis. J Comp Neurol. 1995;352:161–86.
Mahmmoud RR, Sase S, Aher YD, Sase A, Gröger M, Mokhtar M, et al. Spatial and working memory is linked to spine density and mushroom spines. PLoS ONE. 2015;10:e0139739.
Vialou V, Robison AJ, Laplant QC, Covington HE 3rd, Dietz DM, Ohnishi YN, et al. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci. 2010;13:745–52.
Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med. 2013;19:337.
Sun H, Damez-Werno DM, Scobie KN, Shao N-Y, Dias C, Rabkin J, et al. ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior. Nat Med. 2015;21:1146–53.
Jiang C, Lin WJ, Sadahiro M, Labonté B, Menard C, Pfau ML, et al. VGF function in depression and antidepressant efficacy. Mol Psychiatry. 2018;23:1632–42.
Hering H, Sheng M. Dentritic spines: structure, dynamics and regulation. Nat Rev Neurosci. 2001;2:880–8.
Spruston N. Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci. 2008;9:206.
Bak M, Silahtaroglu A, Møller M, Christensen M, Rath MF, Skryabin B, et al. MicroRNA expression in the adult mouse central nervous system. RNA. 2008;14:432–44.
Bala S, Csak T, Momen-Heravi F, Lippai D, Kodys K, Catalano D. et al. Biodistribution and function of extracellular miRNA-155 in mice. Sci Rep. 2015;5:10721.
Laulagnier K, Javalet C, Hemming FJ, Sadoul R. Purification and analysis of exosomes released by mature cortical neurons following synaptic activation. In: Hill AF, editor. Exosomes and microvesicles: methods and protocols. New York: Springer New York; 2017. pp 129–38.
Chisholm D, Sweeny K, Sheehan P, Rasmussen B, Smit F, Cuijpers P, et al. Scaling-up treatment of depression and anxiety: a global return on investment analysis. Lancet Psychiatry. 2016;3:415–24.
Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894–902.
Chen RJ, Kelly G, Sengupta A, Heydendael W, Nicholas B, Beltrami S, et al. MicroRNAs as biomarkers of resilience or vulnerability to stress. Neuroscience. 2015;305:36–48.
Small EM, Sutherland LB, Rajagopalan KN, Wang S, Olson EN. MicroRNA-218 regulates vascular patterning by modulation of slit-robo signaling. Circulation Res. 2010;107:1336–44.
Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–6.
Chivet M, Hemming F, Pernet-Gallay K, Fraboulet S, Sadoul R. Emerging role of neuronal exosomes in the central nervous system. Front Physiol. 2012;3:145.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.
Korkut C, Li Y, Koles K, Brewer C, Ashley J, Yoshihara M, et al. Regulation of postsynaptic retrograde signaling by presynaptic exosome release. Neuron. 2013;77:1039–46.
Jensen LA, Reddy LV, Hoye ML, Miller TM, Richard J-P, Rothstein JD, et al. Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis. Brain. 2018;141:2561–75.
Arenaccio C, Chiozzini C, Ferrantelli F, Leone P, Olivetta E, Federico M. Exosomes in therapy: engineering, pharmacokinetics and future applications. Current Drug Targets. 2019;20:87–95.
Sambandan S, Akbalik G, Kochen L, Rinne J, Kahlstatt J, Glock C, et al. Activity-dependent spatially localized miRNA maturation in neuronal dendrites. Science. 2017;355:634–7.
Hoops D, Flores C. Making dopamine connections in adolescence. Trends Neurosci. 2017;40:709–19.
Goldman JS, Ashour MA, Magdesian MH, Tritsch NX, Harris SN, Christofi N. Netrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly. J Neurosci. 2013;33:17278–89.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, et al. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439:283–9.
Radley JJ, Rocher AB, Miller M, Janssen WGM, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cerebral Cortex. 2006;16:313–20.
Bloss EB, Janssen WG, Ohm DT, Yuk FJ, Wadsworth S, Saardi KM, et al. Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. J Neurosci. 2011;31:7831–9.
Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M, et al. A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol. 2009;11:705–16.
Rocchi A, Moretti D, Lignani G, Colombo E, Scholz-Starke J, Baldelli P, et al. Neurite-enriched microRNA-218 stimulates translation of the GluA2 subunit and increases excitatory synaptic strength. Mol Neurobiol. 2019. https://doi.org/10.1007/s12035-019-1492-7
Acknowledgements
This work was funded by the National Institute on Drug Abuse (CF Grant number: R01DA037911), the Canadian Institute for Health Research (CF Grant Number: MOP-74709), the Natural Science and Engineering Research Council of Canada (CF Grant Number: 2982226), and the National Institute of Mental Health (EJN Grant numbers: P50MH096890 and R01MH051399). CF is a research scholar of the Fonds de Recherche du Québec—Santé. ATB received the Integrated Program in Neuroscience fellowship. We thank Dr. Giovanni Hernandez for his help with the revision of the paper, Dr. Elizabeth Ruiz for technical support, and Carlos Torres-Berrío for help in the graphic design. This study used the services of the Molecular and Cellular Microscopy Platform at the Douglas Mental Health University Institute in Montreal, Canada.
Author contributions
ATB and CF designed the project. ATB performed gene expression experiments with mouse brain tissue and blood, stereotaxic surgeries, viral infections, antagomiR infusions, and behavioral experiments. DN and SC performed all the neuroanatomical experiments. EMP performed behavioral experiments. JMR performed gene expression experiments with mouse brain tissue. PL performed stereotaxic surgeries. EJN provided reagents and technical training necessary to perform the research. ATB and CF wrote the paper. CF supervised the project. All authors discussed the results and commented and edited the paper.
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Torres-Berrío, A., Nouel, D., Cuesta, S. et al. MiR-218: a molecular switch and potential biomarker of susceptibility to stress. Mol Psychiatry 25, 951–964 (2020). https://doi.org/10.1038/s41380-019-0421-5
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DOI: https://doi.org/10.1038/s41380-019-0421-5
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