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Endoplasmic reticulum stress protein GRP78 for ketamine's antidepressant effects

Kaydedildi:
Yayımlandı:bioRxiv (Feb 25, 2025)
Yazar: Cui, Wanpeng
Diğer Yazarlar: Chen, Shen, Wen-Cheng, Xiong, Lin, Mei
Baskı/Yayın Bilgisi:
Cold Spring Harbor Laboratory Press
Konular:
Ketamine
Endoplasmic reticulum
Protein folding
Antidepressants
Glutamatergic transmission
Genetic screening
Prefrontal cortex
Online Erişim:Citation/Abstract
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Özet:Ketamine is a fast-acting, long-lasting novel antidepressant. However, underpinning intracellular mechanisms remain unclear. We conducted an unbiased screening for genes that were less expressed in the prefrontal cortex (PFC) of mice that did not display antidepression-like effects to ketamine. GO analysis implicated endoplasmic reticulum and protein folding; in particular, GRP78, a stress-induced chaperone protein critical for protein folding, was reduced. We showed that GRP78 deficiency in PFC neurons induced depressive-like behaviors, whereas its overexpression produced anti-depression-like effects, revealing a novel function of GRP78. Prefrontal GRP78 was necessary for ketamine's antidepressant-like effects. GRP78 was also required for ketamine to increase calcium activity and glutamatergic transmission. Enhancing GRP78 by viral infection and azoramide enabled non-responsive mice to respond to ketamine. Together, our results demonstrate that GRP78 is critical for ketamine to execute antidepressant effects by potentiating glutamatergic transmission in the PFC.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE289896
ISSN:2692-8205
DOI:10.1101/2025.02.22.639685
Kaynak:Biological Science Database