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

Molecular Psychiatry volume 26, pages 4742–4753 (2021)Cite this article

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Abstract

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.

Data availability

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 availability

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).

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Acknowledgements

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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  1. These authors contributed equally: Atom J. Lesiak, Kevin Coffey

Authors and Affiliations

  1. Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, 98104, USA

    Atom J. Lesiak, Kevin Coffey, Katharine J. Liang & John F. Neumaier

  2. Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA

    Joshua H. Cohen, Charles Chavkin & John F. Neumaier

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  6. John F. Neumaier
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Contributions

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). https://doi.org/10.1038/s41380-020-0750-4

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