GPR17 modulates anxiety-like behaviors via basolateral amygdala to ventral hippocampal CA1 glutamatergic projection

Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injur...

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Published in:Acta pharmaceutica Sinica. B 2024-11, Vol.14 (11), p.4789-4805
Main Authors: Nie, Ruizhe, Zhou, Xinting, Fu, Jiaru, Hu, Shanshan, Zhang, Qilu, Jiang, Weikai, Yan, Yizi, Cao, Xian, Yuan, Danhua, Long, Yan, Hong, Hao, Tang, Susu
Format: Article
Language:English
Subjects:
Anxiety
Basolateral amygdala
Cangrelor
CRS
Glutamatergic neurons
Glutamatergic projection
GPR17
Original
Ventral hippocampal CA1
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Summary:Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders. However, no study has investigated the role of GPR17 in psychiatric disorders. In a well-established chronic restraint stress (CRS) mouse model, using a combination of pharmacological and molecular biology techniques, viral tracing, in vitro electrophysiology recordings, in vivo fiber photometry, chemogenetic manipulations and behavioral tests, we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala (BLA) glutamatergic neurons. Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutamatergic neurons effectively improved anxiety-like behaviors. Overexpression of GPR17 in BLA glutamatergic neurons increased the susceptibility to anxiety-like behaviors. What's more, BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors via BLA to ventral hippocampal CA1 glutamatergic projection. Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders. Downregulation of GPR17 in BLA glutamatergic neurons alleviates anxiety-like behaviors by inhibiting BLA glutamatergic neuronal excitability, reducing the release of glutamate, and weakening the glutamatergic projection from BLA to vCA1. [Display omitted]
ISSN:2211-3835
2211-3843
DOI:10.1016/j.apsb.2024.08.005