The crucial role of reelin in a preclinical model of depression

Abstract

Depression is a complex psychiatric disorder characterized by a cyclical disease course with repeated episode relapses. Rats treated for 21 days with corticosterone (CORT), a well characterized model of depression, exhibit a depression-like phenotype. Additionally, CORT treated rats have shown a downregulation in reelin. Reelin is a large glycoprotein that has been implicated in many psychiatric illnesses. Reelin is involved in stimulating the growth of dendrites, guiding neuronal migration, and regulating synaptogenesis. The goal of these experiments was to investigate the involvement of reelin in depression using the CORT model. In the first experiment, reelin downregulation in an animal model of recurrent depression was assessed using chronic and intermittent CORT administration (three cycles, each one followed by a recovery period), and whether there was a correlation between reelin expression in the dentate gyrus (DG) subgranular zone (SGZ) and depression-like behaviour, namely immobility in the forced swim test (FST). In the second experiment, the potential antidepressant effect of reelin (at either 3μg or 5μg either every 5 or 10 days) via lateral tail vein injections on depressive-like behaviour and reelin expression in the SGZ was assessed in the CORT model, and the correlation between reelin downregulation and immobility was again investigated. CORT produced an increase in depression-like behaviour in both experiments. In the first experiment, FST immobility of rats that received CORT recovered to baseline level after the first cycle, but did not recover after the third. Reelin was downregulated in the SGZ after CORT injections at all time points in the first cycle, and this downregulation was more pronounced in cycle three. As hypothesized, increased FST immobility was negatively correlated with decreased number of reelin-positive cells. When administered reelin, the deleterious CORT-induced behavioural and neurobiological effects were normalised. These studies provide evidence that repeated and intermittent CORT treatment can be used as an animal model of recurrent depression. Furthermore, they reinforce the idea that reelin downregulation is implicated as an important neurochemical event underlying the depressive-like phenotype, and show for the first time that peripheral reelin has antidepressant or neuroprotective effects in the brain, although the mechanism of action is not yet known.