Antidepressant effects of repeated s-ketamine administration as NMDAR Antagonist: Involvement of CaMKIIα and mTOR signaling in the hippocampus of CUMS mice

With the approval of s-ketamine nasal spray as a novel antidepressant, its robust antidepressant effects have been intensively examined in clinical trials. However, the therapeutic efficacy and mechanisms of repeated intermittent drug administration remain unclear. In the present study, we applied a classic chronic unpredictable mild stress (CUMS) model to induce depressive-like behaviors of mice and evaluated the role of repeated s-ketamine administration (10 mg/kg, 7 consecutive days) in ameliorating depressive-like behaviors and modulating related molecular pathways. A battery of behavioral tests were performed to assess CUMS-induced depression. The protein expressions of GluN1, GluN2A, GluN2B, GluR1, CaMKIIa, phosphorylated CaMKIIa (p-CaMKIIa), BDNF, TrkB, phosphorylated TrkB (p-TrkB), mTOR, and phosphorylated mTOR (p-mTOR) as well as modification of synaptic ultrastructure was identified in hippocampal tissues. It turned out that s-ketamine manifested evident antidepressant effects with improved synaptic plasticity. Meanwhile, the results suggested that s-ketamine could differentially modulate glutamate receptors with upregulated GluN1 and GluR1 levels and downregulated GluN2B levels. CUMS-induced elevation of CaMKIIa phosphorylation and decline of BDNF, TrkB phosphorylation and mTOR could also be reversed through s-ketamine treatment. Together, our study provided evidence that selectively modulated glutamate receptors as well as CaMKIIa and mTOR signaling were involved in repeated sketamine administration.

Automated summary

Through experiments on mice, it was found that repeated intermittent administration of s-ketamine nasal spray can improve depressive-like behaviors and modulate related molecular pathways, including the modification of synaptic ultrastructure. The study showed that s-ketamine can reverse the elevated phosphorylation of CaMKIIa and the decreased levels of BDNF, TrkB phosphorylation, and mTOR induced by CUMS by upregulating GluN1 and GluR1 levels and downregulating GluN2B levels. These findings provide evidence that selectively modulated glutamate receptors, CaMKIIa, and mTOR signaling play a role in repeated s-ketamine administration.