Resilient and vulnerable rats to acute foot shock stress show different glial cell responses: possible rescue of pathological alterations by a single ketamine administration

Background Acute traumatic experiences trigger neurobiological changes in the brain. In vulnerable subjects, such alterations persist and lead to the development of psychiatric conditions [1]. Neuronal alterations have mostly been studied [1,2] leaving aside glial cells, that instead play key roles in brain homeostasis [3]. By using a validated animal model, we studied the differential impact of traumatic stress on cortical glial cells of resilient (RES) and vulnerable (VUL) rats [2]. To test a possible translationally relevant rescue strategy, we administered the rapid antidepressant ketamine 24h after stress and rat cortices were analyzed 24h later. Methods Adult Sprague-Dawley rats were exposed to a single footshock stress (FS, 40 min-intermittent, 0.8 mA[2]). Rats showing anhedonia, measured by reduction in 1h-sucrose (1%) intake ≥25% compared to baseline (BL: 4 week-mean intake before FS), were identified as VUL, while rats showing ≤10% change were considered RES. Markers of both glial cells and neurons morphology and functions as well as of neuroinflammation were studied in cortices (n=4-6/group, collected 24h or 48h after FS) by RT-PCR, western blotting and immunofluorescence, and analyzed by one-way ANOVA followed by Tukey’s test. Ketamine (10 mg/kg; i.p.)- and vehicle-treated rats were compared by Student’s t test; p≤0.05 was considered significant. Results VUL displayed robust and prolonged anhedonic-like behavior after FS. Astrocytes were reactive 24h after FS in stressed rats, without changes in the dendritic marker MAP2. Reactive astrocytes and microglia and elevation in parameters of inflammation were observed 48h after FS selectively in VUL with activation of the NFkB pathway. VUL also showed reduced MAP2 expression. Ketamine dampened microglia reactivity and neuroinflammation with reduced activation of the NFkB pathway in VUL, also rescuing MAP2 expression, while in RES did not affect such parameters in RES. Conclusions This study suggests that acute stress affects glial cells and that their responses are different in RES and VUL rats, and that Ketamine treatment could be beneficial to turn off the pathological process triggered by stress. Data collected lays the foundations for future studies with diagnostic and therapeutic implications having glial cell function as target.