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Sequencing the serotonergic neuron translatome reveals a new role for Fkbp5 in stress


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.

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Fig. 1: Experimental design and repeated forced swim stress.
Fig. 2: Differential expression of stress-sensitive genes.
Fig. 3: Enrichment and noise filtering of stress-sensitive and serotonergic neuron specific RNA-seq data.
Fig. 4: Repeated forced swim stress increased Fkbp5 hybridization signal in Pet1 neurons in the dorsal raphe.
Fig. 5: Inhibition of FKBP51 in the dorsal raphe with SAFit2 blocks stress-induced reduction in sucrose consumption.

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  1. 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.

    Article  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. Ebner K, Singewald N. Individual differences in stress susceptibility and stress inhibitory mechanisms. Curr Opin Behav Sci. 2017;14:54–64.

    Article  Google Scholar 

  4. Klengel T, Binder EB. Gene—environment interactions in major depressive disorder. Can J Psychiatry. 2013;58:76–83.

    Article  PubMed  Google Scholar 

  5. Klengel T, Dias BG, Ressler KJ. Models of intergenerational and transgenerational transmission of risk for psychopathology in mice. Neuropsychopharmacology. 2016;41:219–31.

    Article  PubMed  Google Scholar 

  6. Rubinow DR, Schmidt PJ. Sex differences and the neurobiology of affective disorders. Neuropsychopharmacology. 2018;26:85.

    Google Scholar 

  7. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  PubMed  Google Scholar 

  10. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369–88.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

  14. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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.

    CAS  Google Scholar 

  18. Matosin N, Halldorsdottir T, Binder EB. Understanding the molecular mechanisms underpinning gene by environment interactions in psychiatric disorders: the FKBP5 model. BPS. 2018.

  19. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Coffey KR, Barker DJ, Ma S, West MO. Building an open-source robotic stereotaxic instrument. J Vis Exp. 2013;80:e51006.

    Google Scholar 

  26. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  Google Scholar 

  30. Lalovic A, Turecki G. Meta-analysis of the association between tryptophan hydroxylase and suicidal behavior. Am J Med Genet. 2002;114:533–40.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zannas AS, Wiechmann T, Gassen NC, Binder EB. Gene–stress–epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology. 2016;41:261–74.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  PubMed  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Article  Google Scholar 

  41. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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.

    Google Scholar 

  43. 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.

    Google Scholar 

  44. 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.

  45. 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.

    Google Scholar 

  46. 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.

    Article  PubMed  CAS  Google Scholar 

  47. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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.

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations



AJL and KC performed the majority of the experiments, data processing, and data analysis. JHC and KJL helped perform experiments. AJL, JHC, CC, and JFN helped develop the initial experimental plan, and KC was essential for data analysis and follow-up experiments with AJL and JFN after first cohort of RNA-seq. Manuscript was written by AJL, KC, and JFN.

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Correspondence to John F. Neumaier.

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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).

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