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Cholecystokinin B receptor antagonists for the treatment of depression via blocking long-term potentiation in the basolateral amygdala

Molecular Psychiatry volume 28, pages 3459–3474 (2023)Cite this article

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Abstract

Depression is a common and severe mental disorder. Evidence suggested a substantial causal relationship between stressful life events and the onset of episodes of major depression. However, the stress-induced pathogenesis of depression and the related neural circuitry is poorly understood. Here, we investigated how cholecystokinin (CCK) and CCKBR in the basolateral amygdala (BLA) are implicated in stress-mediated depressive-like behavior. The BLA mediates emotional memories, and long-term potentiation (LTP) is widely considered a trace of memory. We identified that the cholecystokinin knockout (CCK-KO) mice impaired LTP in the BLA, while the application of CCK4 induced LTP after low-frequency stimulation (LFS). The entorhinal cortex (EC) CCK neurons project to the BLA and optogenetic activation of EC CCK afferents to BLA-promoted stress susceptibility through the release of CCK. We demonstrated that EC CCK neurons innervate CCKBR cells in the BLA and CCK-B receptor knockout (CCKBR-KO) mice impaired LTP in the BLA. Moreover, the CCKBR antagonists also blocked high-frequency stimulation (HFS) induced LTP formation in the BLA. Notably, CCKBR antagonists infusion into the BLA displayed an antidepressant-like effect in the chronic social defeat stress model. Together, these results indicate that CCKBR could be a potential target to treat depression.

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Fig. 1: CCK signaling is critical for LTP induction in the BLA.
Fig. 2: Optogenetic activation of the ECcck–BLA circuit with SSDS induced depressive-like behaviors.
Fig. 3: ECCCK-BLA circuit-specific knockdown of CCK impaired the optogenetic activation-induced stress susceptibility.
Fig. 4: CSDS activated CCKBR neurons in the BLA.
Fig. 5: LTP deficit in CCKBR-KO mice and YM022 blocked LTP in the BLA.
Fig. 6: Antidepressant effects of YM022 in CSDS model.
Fig. 7: Antagonizing BLA CCKBR mediates antidepressant-like effects.

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Acknowledgements

This work was supported by: Hong Kong Research Grants Council, General Research Fund: 11103220, 11101521, 11102422; (GRF, JFH) Hong Kong Research Grants Council, Collaborative Research Fund: C1043-21GF; (CRF, JFH) Innovation and Technology Fund: MRP/053/18X, GHP_075_19GD; (ITF, JFH) Health and Medical Research Fund: 06172456, 09203656; (HMRF, XC, JFH) and the following charitable foundations for their generous support to JFH: Wong Chun Hong Endowed Chair Professorship, Charlie Lee Charitable Foundation, and Fong Shu Fook Tong Foundation.

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  1. These authors contributed equally: Xu Zhang, Muhammad Asim, Wei Fang.

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  1. Department of Neuroscience, City University of Hong Kong, Kowloon Tong, 0000, Hong Kong SAR, PR China

    Xu Zhang, Muhammad Asim, Wei Fang, Hossain Md Monir, Huajie Wang, Kyuhee Kim, Hemin Feng, Shujie Wang, Qianqian Gao, Yuanying Lai & Jufang He

  2. Department of Biomedical Science, City University of Hong Kong, Kowloon Tong, 0000, Hong Kong SAR, PR China

    Xu Zhang, Muhammad Asim, Wei Fang, Hossain Md Monir, Huajie Wang, Kyuhee Kim, Hemin Feng, Shujie Wang, Qianqian Gao, Yuanying Lai & Jufang He

  3. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Hemin Feng

  4. City University of Hong Kong Shenzhen research institute, Shenzhen, 518507, PR China

    Jufang He

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Contributions

JH, XZ, and MA designed the experiments; XZ, QG, and SW carried out the LTP study. XZ and MA performed the behavior experiments. MA and WF did the viral injections and cannula implantation surgeries. MA conducted optogenetic and fiber photometry recording experiments. WF, YL, KK, and HF performed histology experiments. MA and HW collected and analyzed the data for the western blotting. HM carried out the BBB penetration experiment. XZ and MA wrote the manuscript. JH assisted in editing and writing the manuscript. JH supervised the project.

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Zhang, X., Asim, M., Fang, W. et al. Cholecystokinin B receptor antagonists for the treatment of depression via blocking long-term potentiation in the basolateral amygdala. Mol Psychiatry 28, 3459–3474 (2023). https://doi.org/10.1038/s41380-023-02127-7

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