Esketamine attenuates post-traumatic stress disorder via suppressing neuroinflammation and abnormal myelination

Post-traumatic stress disorder (PTSD) is a chronic psychological disorder that is induced by traumatic events. The pathophysiological mechanism of PTSD involves complex neurobiological processes. However, the underlying mechanism is not clear, leading to lack of effective therapeutic interventions.

Mice were exposed to the electric foot shocks using the contextual fear memory paradigm. A subanesthetic dose (30 mg/kg) of esketamine or saline was administered via intraperitoneal (i.p.) injection 1 h after the electric foot shocks. Fear retrieval was tested on day 1 and day 7 after fear conditioning. Anxiety-like and depressive-like behaviors were evaluated using the open field test and elevated plus maze on day 1 and day 2, respectively, after the foot-shocks. The medial prefrontal cortex (mPFC) was freshly collected 1 h after esketamine administration following the foot-shocks for RNA sequencing. Additionally, the mPFC were collected 4 days after fear conditioning and subjected to quantitative real-time PCR (qPCR) analysis and immunofluorescence staining.

A single subanesthetic dose of esketamine significantly alleviated PTSD-like symptoms in mice induced by electric foot-shocks. RNA sequencing revealed the involvement of neuroinflammation and aberrant myelination in the pathogenesis of PTSD. Subsequently, we observed a significant increase in the number of ionized calcium binding adaptor molecule 1 (Iba1)-positive microglial cells and transcriptional upregulation of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), in the mPFC of mice subjected electric foot shocks, indicating elevated neuroinflammation. Subanesthetic esketamine administration significantly attenuated this neuroinflammatory response. Furthermore, electric foot shocks caused significantly increased the expression of myelin basic protein (MBP), myelin-associated glycoprotein (MAG), oligodendrocyte transcription factor 2 (Olig2) and platelet-derived growth factor receptor-α (PDGFRα), suggesting increased myelination associated with PTSD. Esketamine treatment also rescued this abnormal myelination.

Our study demonstrates the contribution of neuroinflammation and abnormal myelination are closely related to the development of PTSD. Moreover, a subanesthetic dose of esketamine alleviated the PTSD-like symptoms in mice by suppressing foot-shock-induced increases in neuroinflammation and myelination. These results highlight the therapeutic potential of subanesthetic esketamine in mitigating PTSD.