Reelin doses normalizing behavioural alterations induced by repeated corticosterone avoid eliciting neuroinflammation-associated morphology in hippocampal microglia

Abstract

Chronic stress elicits widespread, multisystem alterations, among them the increased production of inflammatory mediators by immune cells, that culminate in physiological and psychological disruptions. Microglia are resident macrophages of the CNS that show altered morphology alongside increases in pro-inflammatory cytokine release and phagocytosis in response to chronic stress. Chronic stress-induced behavioural and physiological alterations can be replicated in rats using daily injections of corticosterone (CORT) over a prolonged period. Reelin, a glycoprotein reduced in depression and animal models of chronic stress, rapidly reverses chronic CORT-induced symptoms following a single 3 g injection. However, high levels of reelin may be pro-inflammatory, indicating the need to determine if a dose of reelin that resolves chronic stress-induced impairments exacerbates neuroinflammation as a possible adverse effect of reelin treatment. Using either a single 3 g reelin injection following chronic stress or repeated (3) reelin injections throughout chronic stress in male Long Evans rats, we show that reelin does not promote microglia morphologies indicative of pro-inflammatory function within the context of chronic stress, and that both reelin administration schedules rapidly reverse chronic stress-induced despair-like behaviour. These results offer insight into the effect of peripheral reelin administration on processes underlying neuroinflammation and suggest that restoring reelin following chronic stress does not exacerbate microglia-driven neuroinflammation. This research together with past research from our lab supports the advancement of reelin or reelin peptides towards clinical evaluation as a rapid antidepressant.