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Mitogen-activated protein kinase dependent presynaptic potentiation in the lateral habenula mediates depressive-like behaviors in rats

Neuropsychopharmacology volume 50, pages 540–547 (2025)Cite this article

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Abstract

Emerging evidence suggests that the enhanced activity of lateral habenula (LHb) is involved in depressive disorders. This abnormal potentiation of LHb neurons was shown to originate from presynaptic alterations; however, the mechanisms underlying this presynaptic enhancement and physiological consequences are yet to be elucidated. Previously, we reported that presynaptic transmission in the LHb is temporally rhythmic, showing greater activity in the afternoon than in the morning. Here, we used a learned helpless rodent model of depression to show that exposure to a stressor or incubation with the stress hormone, corticosterone, abolished the presynaptic temporal variation in the LHb. In addition, selective inhibition of mitogen-activated protein kinase (MAPK) kinase (MAPKK, MEK) activity in the LHb restored the presynaptic alteration even after stress exposure. Moreover, we observed a slight increase in phosphorylated synapsin I after stress exposure. Finally, we found that a blockade of MAPK signaling before stress exposure successfully prevented the depression-like behaviors, including behavioral despair and helplessness, in an acute learned helpless animal model of depression. Our study delineates the cellular and molecular mechanisms responsible for the abnormal presynaptic enhancement of the LHb in depression, which may mediate depressive behaviors.

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Fig. 1: The exposure to stressor disrupts temporal variation in the Pr of LHb neurons.
Fig. 2: Presynaptic potentiation of the LHb after CORT incubation is mediated by the MAPK pathway.
Fig. 3: Phosphorylation of synapsin I in the LHb is increased after stress exposure.
Fig. 4: Depression-like behaviors after exposure to a stressor are attenuated by a single MAPK inhibitor infusion selective to the LHb.

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All data generated or analyzed in the study are included in the published article or its Supplementary Information files.

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Acknowledgements

We would like to thank Dr. Taejoon Kim for performing the western blot experiments. This research was supported by the National Research Foundation of Korea (NRF-NRF-2020R1A2C2005868 to C.C.; NRF-2022R1C1C2008960 to H.P.).

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  1. Department of Biological Sciences, Konkuk University, Seoul, South Korea

    Hoyong Park, Hakyun Ryu, Seungjae Zhang, Sungmin Kim & ChiHye Chung

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Contributions

C.C. conceived this work and designed the experiments. H.P., H.R., S.Z., and S.K. performed experiments and acquired the data. H.P., H.R., and C.C. analyzed and interpreted the data. H.P. and C.C. prepared figures and wrote the manuscript. All authors have approved the final version of the manuscript.

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Correspondence to ChiHye Chung.

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Park, H., Ryu, H., Zhang, S. et al. Mitogen-activated protein kinase dependent presynaptic potentiation in the lateral habenula mediates depressive-like behaviors in rats. Neuropsychopharmacol. 50, 540–547 (2025). https://doi.org/10.1038/s41386-024-02025-8

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