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Baicalin Modulates APPL2/Glucocorticoid Receptor Signaling Cascade, Promotes Neurogenesis, and Attenuates Emotional and Olfactory Dysfunctions in Chronic Corticosterone-Induced Depression

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Abstract

Olfactory dysfunction is often accompanied with anxiety- and depressive-like behaviors in depressive patients. Impaired neurogenesis in hippocampus and subventricular zone (SVZ)-olfactory bulb (OB) contribute to anxiety- and depressive-like behaviors and olfactory dysfunctions. However, the underlying mechanisms of olfactory dysfunction remain unclear. Our previous study indicates that adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2 (APPL2), could affect the activity and sensitivity of glucocorticoid receptor (GR) and mediate impaired hippocampal neurogenesis, which contribute the development of depression. In the present study, we further identified the roles of APPL2 in olfactory functions. APPL2 Tg mice displayed higher GR activity and less capacity of neurogenesis at olfactory system with less olfactory sensitivity than WT mice, indicating that APPL2 could be a potential therapeutic target for depression and olfactory deficits. We then studied the effects of baicalin, a medicinal herbal compound, on modulating APPL2/GR signaling pathway for promoting neurogenesis and antidepressant as well as improving olfactory functions. Baicalin treatment inhibited APPL2/GR signaling pathway and improved neurogenesis at SVZ, OB, and hippocampus in APPL2 Tg mice and chronic corticosterone-induced depression mouse model. Behavioral tests revealed that baicalin attenuated depressive- and anxiety-like behaviors and improve olfactory functions in the chronic depression mouse model and APPL2 Tg mice. Taken together, APPL2 could be a novel therapeutic target for improving depressant-related olfactory dysfunctions and baicalin could inhibit APPL2-mediated GR hyperactivity and promote adult neurogenesis, subsequently releasing depressive and anxiety symptoms and improving olfactory functions for antidepressant therapy.

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Acknowledgements

We truly appreciate the technology supports of Dr. Guo Jing and Mr. Jacky HUNG in Core facility HKU, the technology on dSTORM and Imaris software processing.

Funding

This work was supported by RGC GRF grants from Hong Kong Research Grants Council (GRF No. 777313M, 776512M, J.S.), RGC AoE/P-705/16, and Contract Research Grant with Beijing Tong Ren Tang Chinese Medicine Co., LTd.

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Authors and Affiliations

  1. School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sasssoon Road, Hong Kong, Hong Kong SAR, China

    Chong Gao, Qiaohui Du, Wenting Li, Ruixia Deng & Jiangang Shen

  2. Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China

    Qi Wang

  3. Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sasson Road, Hong Kong, Hong Kong SAR, China

    Aimin Xu

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  1. Chong Gao
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Correspondence to Jiangang Shen.

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Gao, C., Du, Q., Li, W. et al. Baicalin Modulates APPL2/Glucocorticoid Receptor Signaling Cascade, Promotes Neurogenesis, and Attenuates Emotional and Olfactory Dysfunctions in Chronic Corticosterone-Induced Depression. Mol Neurobiol 55, 9334–9348 (2018). https://doi.org/10.1007/s12035-018-1042-8

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