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Hippocampal BMP signaling as a common pathway for antidepressant action

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Abstract

The benefits of current treatments for depression are limited by low response rates, delayed therapeutic effects, and multiple side effects. Antidepressants affect a variety of neurotransmitter systems in different areas of the brain, and the mechanisms underlying their convergent effects on behavior have been unclear. Here we identify hippocampal bone morphogenetic protein (BMP) signaling as a common downstream pathway that mediates the behavioral effects of five different antidepressant classes (fluoxetine, bupropion, duloxetine, vilazodone, trazodone) and of electroconvulsive therapy. All of these therapies decrease BMP signaling and enhance neurogenesis in the hippocampus. Preventing the decrease in BMP signaling blocks the effect of antidepressant treatment on behavioral phenotypes. Further, inhibition of BMP signaling in hippocampal newborn neurons is sufficient to produce an antidepressant effect, while chemogenetic silencing of newborn neurons prevents the antidepressant effect. Thus, inhibition of hippocampal BMP signaling is both necessary and sufficient to mediate the effects of multiple classes of antidepressants.

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Acknowledgements

We thank Dr. Jennifer A. Kearney and Dr. Nicole A. Hawkins for their advice on Electroconvulsive Therapy (Basic auricular electroconvulsive test-ECT) and for sharing their ECT Unit # 57800-001: UGO BASILE Biological Research Apparatus with us. We acknowledge the assistance of the Northwestern University Behavioral Phenotyping Core facility.

Funding

This work was supported by NIH Grant R01 MH114923 to JAK and by the Davee Foundation.

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Authors and Affiliations

  1. Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA

    Elif Tunc-Ozcan, Sarah M. Brooker, Jacqueline A. Bonds, Yung-Hsu Tsai, Radhika Rawat, Tammy L. McGuire, Chian-Yu Peng & John A. Kessler

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  1. Elif Tunc-Ozcan
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ETO designed and performed experiments, interpreted the data, and wrote the manuscript. SMB designed and performed experiments and edited the manuscript. JAB performed experiments and edited the manuscript. YT helped with immunohistochemistry. RR helped with in situ hybridization and data analysis. TLM prepared lentivirus and supervised lentivirus experiments. CP and JAK supported the studies with key experimental suggestions, research design, data interpretation, and manuscript preparation.

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Correspondence to Elif Tunc-Ozcan.

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All animal procedures were approved by the Northwestern University Animal Care and Use Committee.

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Tunc-Ozcan, E., Brooker, S.M., Bonds, J.A. et al. Hippocampal BMP signaling as a common pathway for antidepressant action. Cell. Mol. Life Sci. 79, 31 (2022). https://doi.org/10.1007/s00018-021-04026-y

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  • DOI: https://doi.org/10.1007/s00018-021-04026-y

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