[Esketamine alleviates depression-like behaviors in mice with chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex].
Zhuoning Zhang, Xinyu Hao, Fuyang Cao, Yongxin Guo, Shuting Guo, Chen Cai, Weidong Mi, Li Tong
Nan fang yi ke da xue xue bao = Journal of Southern Medical University March 20, 2026 Peer reviewed DOI: 10.12122/j.issn.1673-4254.2026.03.02 via PubMed
Summary
Esketamine reduces depressive-like behaviors in male C57BL/6J mice subjected to chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex (mPFC). Mice treated with esketamine showed significantly reduced immobility in tail suspension and forced swim tests, along with increased sucrose preference. Additionally, chemogenetic activation of mPFC glutamatergic neurons further decreased immobility and increased sucrose preference, while inhibition of these neurons did not produce significant effects.
Study at a glance
| Design | randomized controlled trial |
|---|---|
| Sample size | 150 |
| Population | male C57BL/6J mice subjected to chronic restraint stress |
| Key finding | Esketamine produces antidepressant effects in mice with chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex. |
Abstract
To investigate the regulatory role of glutamatergic neurons in the medial prefrontal cortex (mPFC) in the antidepressant effects of esketamine. A total of 150 male C57BL/6J mice were randomly divided into 15 groups (n=10). The mice subjected to the chronic restraint stress (CRS), and those exhibiting depressive-like behaviors following CRS received either esketamine or saline treatment, and subsequent behavioral changes were evaluated. Depressive-like behaviors were assessed using tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT). The changes in neuronal activity within the mPFC were examined using c-Fos immunofluorescence staining. To explore the underlying mechanism, chemogenetic approaches were employed to specifically modulate the activity of mPFC glutamatergic neurons and examine how these manipulations influenced the effect of esketamine on behaviors of the mice. Compared with saline-treated CRS mice, the mice with esketamine treatment showed significantly reduced immobility time in TST and FST and increased sucrose preference rate. Immunofluorescence staining revealed significantly increased expression of c-Fos in glutamatergic neurons in esketamine-treated mice. Chemogenetic activation of mPFC glutamatergic neurons (hM3Dq group) significantly decreased immobility time of the mice in the TST and FST and increased their sucrose preference as compared with the mice in mCherry group (P<0.01), while inhibition of the mPFC glutamatergic neurons (hM4Di group) produced no significant effect. Among the mice treated with esketamine, those in hM4Di group exhibited significantly increased immobility time in TST and FST and decreased sucrose preference compared with those in mCherry group, while the mice in hM3Dq group showed no such changes. Esketamine produces antidepressant effects in mice with CRS by activating glutamatergic neurons in the mPFC.