Nuclear factor of activated T cells 4 in the prefrontal cortex is required for prophylactic actions of (R)-ketamine

Li Ma,Long Wang,Jiancheng Zhang,Xingming Wang,Yuko Fujita,Tamaki Ishima,Xiayun Wan,Kenji Hashimoto,Youge Qu,Kenta Kobayashi,Jiajing Shan

doi:10.1038/s41398-022-01803-6

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.

Highlights

Robust antidepressant action of the N-methyl-D-aspartate receptor (NMDAR) antagonist (R, S)-ketamine is a paradigm shift for depression research and treatment [1]
We previously reported that LPS caused the splenomegaly and blood levels of IL-6, tumor necrosis factor-α (TNF-α)) from three groups (Fig. 3B, C), the increased ratio of spleen weight to body weight in the mice, indicating that Nfatc4 expression in the prefrontal cortex (PFC) may be associated and that spleen weight was associated with systemic inflamma- with systemic inflammation
The roles of TrkB in the prophylactic effects of (R)-ketamine in LPS model We previously reported the role of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-receptor-kinase B (TrkB) signaling in the beneficial actions of (R)-ketamine [32, 37, 53,54,55,56]

Summary

Introduction

Robust antidepressant action of the N-methyl-D-aspartate receptor (NMDAR) antagonist (R, S)-ketamine is a paradigm shift for depression research and treatment [1]. In 2000, Berman et al [2] demonstrated the rapid-onset and sustained antidepressant actions of (R, S)-ketamine in patients with major depressive disorder (MDD). Several groups replicated the robust antidepressant effects of (R, S)-ketamine in treatmentresistant patients with MDD or bipolar disorder (BD) [3,4,5,6,7,8,9,10]. (R, S)-ketamine can produce the robust antidepressant actions in severe patients with depression, precise molecular mechanisms underlying its antidepressants remain elusive [14,15,16,17,18,19,20,21,22]. The precise molecular and cellular mechanisms underlying prophylactic actions of (R, S)-ketamine remain unclear

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