STAT3 induces amygdala apoptosis by regulating the expression of stathmin in the rat model of posttraumatic stress disorder

Introduction:
Stathmin, recognised as the protein associated with the disassembly of microtubules, plays a vital role in the modulation of human fear as well as anxiety responses. However, it is unclear whether stathmin regulates the specific mechanism of disruption of fear-associated memory resulting from posttraumatic stress disorder (PTSD). This study aims to observe the impact of stathmin on deficit in fear-based memory during PTSD and investigate the underlying mechanisms involved, in order to establish an empirical foundation for elucidating the molecular mechanisms underlying the pathogenesis of PTSD.

Material and methods:
We used an single prolonged stress (SPS) protocol to induce the PTSD in the rat model. Open field test and forced swimming test were used to examine the anxious and fearful behaviours exhibited by the rats. STAT3/stathmin signalling-related expressions were assessed through immunofluorescence, immunohistochemical, RT-qPCR and Western blotting. Stathmin and STAT3 binding activity was detected by molecular docking. Amygdala apoptosis was detected by TUNEL staining.

Results:
In this study, while stathmin gene expression in amygdala was significantly downregulated, after 7 days of SPS, activation of STAT3 was observed in the rats’ amygdala, accompanied by a notable increase in the apoptosis rate. Consequently, the rats exhibited heightened fear and anxiety responses. However, the above results were reversed after overexpression of the stathmin gene. In addition, following the administration of the STAT3 inhibitor, WP1066, there was a notable reduction in the apoptosis rate, leading to decreased levels of fear and anxiety in rats exposed to SPS. In rats exposed to SPS, administered WP1066, and injected with adenovirus expressing stathmin-targeted siRNA into the amygdala to make the inhibition of stathmin expression partially counteracted the protective effect of WP1066.

Conclusions:
The findings above suggest that SPS could potentially modulate the stathmin gene’s expression by activating the STAT3 pathway, subsequently leading to apoptosis in amygdala cells. This sequence of events ultimately contributes to the PTSD rat model fear memory impairment.