Esketamine ameliorates depression-like behavior in mice via modulation of the NRG1-ErbB4 pathway.
Hang Yu, Yuqiong Zhu, Jie Wang, Yifan He, Hui Li, Shuxuan Li, Ning Wang, Nuo Chen, Juan Chen, Hongtao Song, Mingjie Zhang, Wenjuan Wang
Frontiers in psychiatry January 1, 2026 Peer reviewed DOI: 10.3389/fpsyt.2026.1722336 via PubMed
Summary
Esketamine demonstrates a significant and rapid antidepressant effect in mice subjected to Chronic Social Defeat Stress (CSDS). After receiving a subanesthetic dose of esketamine, susceptible mice showed improved social interaction and reduced immobility time. Notably, NRG1 levels in the prefrontal cortex increased significantly after 30 minutes post-injection, while GAD67 and ErbB4 expression levels remained unchanged. This suggests that esketamine may regulate the NRG1-ErbB4 signaling pathway to alleviate depressive-like behavior.
Study at a glance
| Design | experimental study |
|---|---|
| Population | mice subjected to Chronic Social Defeat Stress |
| Key finding | The subanesthetic dose of esketamine may regulate the NRG1-ErbB4 signaling pathway and improve depressive-like behavior in mice. |
Abstract
Esketamine has a significant and rapid antidepressant effect. Although studies have shown that Neuregulin 1 (NRG1) and it's signaling pathway are associated with depression, the possible regulatory relationship of esketamine on the NRG1-ErbB4 pathway is not yet clear. To induce depressive-like behavior in mice, a Chronic Social Defeat Stress (CSDS) model was established. Behavioral indicators were then employed to assess depression in these mice, categorized into control, susceptible, and resilient groups. Following intraperitoneal injection of a subanesthetic dose of esketamine, behavioral tests were conducted at 30 minutes and 24 hours post-injection to observe any improvements in depressive-like behavior. Additionally, changes in immunofluorescence and protein expression levels of NRG1-ErbB4 and GAD67 in the prefrontal cortex were evaluated. Compared with the control group, the CSDS susceptible group mice showed decreases in social interaction ratio in the contact area, sucrose preference ratio, NRG1 immunofluorescence protein expression in the prefrontal cortex and NRG1 expression in tissue homogenate; showed significant increases in immobility time; the expression of NRG1 decreased;no significant change in GAD67 and ErbB4 expression level. in After 30 minutes of intraperitoneal injection of esketamine, the expression of NRG1 in the prefrontal cortex of susceptible mice increased significantly. no significant change in GAD67 and ErbB4 expression level. After 30 minutes and 24 hours of intraperitoneal injection of esketamine, the social interaction ratio of susceptible group improved compared to the control group, and the duration of forced swimming immobility was significantly shortened. The subanesthetic dose of esketamine may regulate the NRG1-ErbB4 signaling pathway and improve depressive like behavior in mice.