In:
Translational Psychiatry, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2022-01-21)
Abstract:
( R, S )-ketamine has prophylactic antidepressant-like effects in rodents; however, the precise molecular mechanisms underlying its action remain unknown. Using RNA-sequencing analysis, we searched novel molecular target(s) that contribute to the prophylactic effects of ( R )-ketamine, a more potent enantiomer of ( R, S )-ketamine. Pretreatment with ( R )-ketamine (10 mg/kg, 6 days before) significantly ameliorated body weight loss, splenomegaly, and increased immobility time of forced swimming test in lipopolysaccharide (LPS: 1.0 mg/kg)-treated mice. RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent IPA (Ingenuity Pathway Analysis) revealed that the nuclear factor of activated T cells 4 (NFATc4) signaling might contribute to sustained prophylactic effects of ( R )-ketamine. Quantitative RT-PCR confirmed that ( R )-ketamine significantly attenuated the increased gene expression of NFATc4 signaling ( Nfatc4, Cd4, Cd79b, H2-ab1 , H2-aa ) in the PFC of LPS-treated mice. Furthermore, pretreatment with NFAT inhibitors (i.e., NFAT inhibitor and cyclosporin A) showed prophylactic effects in the LPS-treated mice. Similar to ( R )-ketamine, gene knockdown of Nfatc4 gene by bilateral injection of adeno-associated virus (AAV) into the mPFC could elicit prophylactic effects in the LPS-treated mice. In conclusion, our data implicate a novel NFATc4 signaling pathway in the PFC underlying the prophylactic effects of ( R )-ketamine for inflammation-related depression.
Type of Medium:
Online Resource
ISSN:
2158-3188
DOI:
10.1038/s41398-022-01803-6
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
2609311-X
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