Serotonin is a key mediator of stress, anxiety, and depression, and novel therapeutic targets within serotonin neurons are needed to combat these disorders. To determine how stress alters the translational profile of serotonin neurons, we sequenced ribosome-associated RNA from these neurons after repeated stress in male and female mice. We identified numerous sex- and stress-regulated genes. In particular, Fkbp5 mRNA, which codes for the glucocorticoid receptor co-chaperone protein FKBP51, was consistently upregulated in male and female mice following stress. Pretreatment with a selective FKBP51 inhibitor into the dorsal raphe prior to repeated forced swim stress decreased resulting stress-induced anhedonia. Our results support previous findings linking FKBP51 to stress-related disorders and provide the first evidence suggesting that FKBP51 function may be an important regulatory node integrating circulating stress hormones and serotonergic regulation of stress responses.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Molecular Psychiatry Open Access 14 September 2022
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Data used for figure generation and statistical comparisons are available at https://github.com/DrCoffey/Manuscripts/tree/master/Sequencing%20the%20Serotonin%20Translatome%20(Molecular%20Psychiatry%202020).
Code used for figure generation and statistical comparisons are available at https://github.com/DrCoffey/Manuscripts/tree/master/Sequencing%20the%20Serotonin%20Translatome%20(Molecular%20Psychiatry%202020).
Stone DM, Simon TR, Fowler KA, Kegler SR, Yuan K, Holland KM, et al. Vital signs: trends in state suicide rates—United States, 1999-2016 and circumstances contributing to suicide—27 states, 2015. Mob Mortal Wkly Rep. 2018;67:617–24.
Reul JMHM, Collins A, Saliba RS, Mifsud KR, Carter SD, Gutierrez-Mecinas M, et al. Glucocorticoids, epigenetic control and stress resilience. Neurobiol Stress. 2015;1:44–59.
Ebner K, Singewald N. Individual differences in stress susceptibility and stress inhibitory mechanisms. Curr Opin Behav Sci. 2017;14:54–64.
Klengel T, Binder EB. Gene—environment interactions in major depressive disorder. Can J Psychiatry. 2013;58:76–83.
Klengel T, Dias BG, Ressler KJ. Models of intergenerational and transgenerational transmission of risk for psychopathology in mice. Neuropsychopharmacology. 2016;41:219–31.
Rubinow DR, Schmidt PJ. Sex differences and the neurobiology of affective disorders. Neuropsychopharmacology. 2018;26:85.
Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA. 1997;94:5308–13.
Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157:1445–52.
Oquendo MA, Sullivan GM, Sudol K, Baca-Garcia E, Stanley BH, Sublette ME, et al. Toward a biosignature for suicide. Am J Psychiat. 2014;171:1259–77.
Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369–88.
Penn E, Tracy DK. The drugs don’t work? Antidepressants and the current and future pharmacological management of depression. Ther Adv Psychopharmacol. 2012;2:179–88.
Issler O, Haramati S, Paul ED, 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.
Kang SS, Ebbert MTW, Baker KE, Cook C, Wang X, Sens JP, et al. Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J Exp Med. 2018. https://doi.org/10.1084/jem.20180653.
Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR, Ma G, et al. Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell. 2008;135:749–62.
Heiman M, Schaefer A, Gong S, Peterson JD, Day M, Ramsey KE, et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell. 2008;135:738–48.
Sanz E, Yang L, Su T, Morris DR, McKnight GS, Amieux PS. Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc Natl Acad Sci Usa. 2009;106:13939–44.
Rao S, Yao Y, Ryan J, Li T, Wang D, Zheng C, et al. Common variants in FKBP5 gene and major depressive disorder (MDD) susceptibility: a comprehensive meta-analysis. Nat Publ Group. 2016;6:32687.
Matosin N, Halldorsdottir T, Binder EB. Understanding the molecular mechanisms underpinning gene by environment interactions in psychiatric disorders: the FKBP5 model. BPS. 2018. https://doi.org/10.1016/j.biopsych.2018.01.021.
Scott MM, Wylie CJ, Lerch JK, Murphy R, Lobur K, Herlitze S, et al. A genetic approach to access serotonin neurons for in vivo and in vitro studies. Proc Natl Acad Sci USA. 2005;102:16472–7.
McLaughlin JP, Marton-Popovici M, Chavkin C. Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci. 2003;23:5674–83.
Lesiak AJ, Brodsky M, Neumaier JF. RiboTag is a flexible tool for measuring the translational state of targeted cells in heterogeneous cell cultures. BioTechniques. 2015;58:308–17.
Afgan E, Baker D, van den Beek M, Blankenberg D, Bouvier D, Cech M, et al. The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. Nucleic Acids Res. 2016;44:W3–10.
Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C. Salmon provides fast and bias-aware quantification of transcript expression. Nat Meth. 2017;14:417–9.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
Coffey KR, Barker DJ, Ma S, West MO. Building an open-source robotic stereotaxic instrument. J Vis Exp. 2013;80:e51006.
Hartmann J, Wagner KV, Gaali S, Kirschner A, Kozany C, Rühter G, et al. Pharmacological inhibition of the psychiatric risk factor FKBP51 has anxiolytic properties. J Neurosci. 2015;35:9007–16.
Conte IL, Hellen N, Bierings R, Mashanov GI, Manneville J-B, Kiskin NI, et al. Interaction between MyRIP and the actin cytoskeleton regulates Weibel-Palade body trafficking and exocytosis. J Cell Sci. 2016;129:592–603.
Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol. 2015;11:33–37.
Bellivier F, Chaste P, Malafosse A. Association between the TPH gene A218C polymorphism and suicidal behavior: a meta‐analysis. Am J Med Genet Part B. 2003;124B:87–91.
Lalovic A, Turecki G. Meta-analysis of the association between tryptophan hydroxylase and suicidal behavior. Am J Med Genet. 2002;114:533–40.
Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M. Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch Gen Psychiatry. 1994;51:34–8.
Okaty BW, Freret ME, Rood BD, Brust RD, Hennessy ML, deBairos D, et al. Multi-Scale molecular deconstruction of the serotonin neuron system. Neuron. 2015;88:774–91.
Zannas AS, Wiechmann T, Gassen NC, Binder EB. Gene–stress–epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology. 2016;41:261–74.
O’Leary JC III, Dharia S, Blair LJ, Brady S, Johnson AG, Peters M, et al. A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51. PLoS ONE. 2011;6:e24840.
Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34:S186–95.
Hartmann J, Wagner KV, Liebl C, Scharf SH, Wang X-D, Wolf M, et al. The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress. Neuropharmacology. 2012;62:332–9.
Albu S, Romanowski CPN, Curzi ML, Jakubcakova V, Flachskamm C, Gassen NC, et al. Deficiency of FK506‐binding protein (FKBP) 51 alters sleep architecture and recovery sleep responses to stress in mice. J Sleep Res. 2013;23:176–85.
Tozzi L, Farrell C, Booij L, Doolin K, Nemoda Z, Szyf M, et al. Epigenetic changes of FKBP5 as a link connecting genetic and environmental risk factors with structural and functional brain changes in major depression. Neuropsychopharmacology. 2018;43:1138–45.
Darby MM, Yolken RH, Sabunciyan S. Consistently altered expression of gene sets in postmortem brains of individuals with major psychiatric disorders. Transl Psychiatry. 2016;6:e890–e890.
Tatro ET, Everall IP, Masliah E, Hult BJ, Lucero G, Chana G, et al. Differential expression of immunophilins FKBP51 and FKBP52 in the frontal cortex of HIV-infected patients with major depressive disorder. J Neuroimmune Pharm. 2009;4:218–26.
Chen H, Wang N, Zhao X, Ross CA, O’Shea KS, McInnis MG. Gene expression alterations in bipolar disorder postmortem brains. Bipolar Disord. 2013;15:177–87.
Sinclair D, Fillman SG, Webster MJ, Weickert CS. Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness. Nat Publ Group. 2013;3:3539.
Roberts S, Keers R, Breen G, Coleman JRI, Jöhren P, Kepa A, et al. DNA methylation of FKBP5 and response to exposure‐based psychological therapy. Am J Med Genet Part B. 2018;36:1982.
Young DA, Inslicht SS, Metzler TJ, Neylan TC, Ross JA. The effects of early trauma and the FKBP5 gene on PTSD and the HPA axis in a clinical sample of Gulf War veterans. Psychiatry Res. 2018. https://doi.org/10.1016/j.psychres.2018.03.037.
Linnstaedt SD, Riker KD, Rueckeis CA, Kutchko KM, Lackey L, McCarthy KR, et al. A functional riboSNitch in the 3′UTR of FKBP5alters microRNA-320a binding efficiency and mediates vulnerability to chronic posttraumatic pain. J Neurosci. 2018;3458:17–49.
Pérez-Ortiz JM, García-Gutiérrez MS, Navarrete F, Giner S, Manzanares J. Gene and protein alterations of FKBP5 and glucocorticoid receptor in the amygdala of suicide victims. Psychoneuroendocrinology. 2013;38:1251–8.
Sabbagh JJ, O’Leary JC III, Blair LJ, Klengel T, Nordhues BA, Fontaine SN, et al. Age-associated epigenetic upregulation of the FKBP5 gene selectively impairs stress resiliency. PLoS ONE. 2014;9:e107241.
Espallergues J, Teegarden SL, Veerakumar A, Boulden J, Challis C, Jochems J, et al. HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience. J Neurosci. 2012;32:4400–16.
Pöhlmann ML, Häusl AS, Harbich D, Balsevich G, Engelhardt C, Feng X, et al. Pharmacological modulation of the psychiatric risk factor FKBP51 alters efficiency of common antidepressant drugs. Front Behav Neurosci. 2018;12:1725.
Funding for these experiments included T32 DA07278 and P50 MH106428. We thank David A. Beck and Cole Trapnell at the University of Washington for consultation on RNA-seq bioinformatics.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Lesiak, A.J., Coffey, K., Cohen, J.H. et al. Sequencing the serotonergic neuron translatome reveals a new role for Fkbp5 in stress. Mol Psychiatry 26, 4742–4753 (2021). https://doi.org/10.1038/s41380-020-0750-4
This article is cited by
Stress decreases serotonin tone in the nucleus accumbens in male mice to promote aversion and potentiate cocaine preference via decreased stimulation of 5-HT1B receptors
Molecular Psychiatry (2022)