We have hypothesized that the extracellular matrix protein reelin is involved in the pathogenesis of major depression. This hypothesis is based on previous work in which we showed that repeated exposure to the stress hormone corticosterone, which increases depression-like behavior in rodents, also decreases the number of reelin+ cells in specific regions of the hippocampus and decreases hippocampal neurogenesis. In addition, we have found that heterozygous reeler mice, which express approximately 50% of normal brain levels of reelin, are more susceptible to the depressogenic effects of corticosterone than their wild-type counterparts. To further understand the relationship between corticosterone, reelin, and depression, we assessed whether the effects of corticosterone on hippocampal reelin expression and neurogenesis parallel the progressive development of depression-like behavior over a 21-day period. Rats were subjected to 7, 14 or 21 days of repeated corticosterone injections (40 mg/kg, s.c.) or vehicle injections followed by behavioral testing, immunohistochemistry, and Golgi analyses. We found that corticosterone-treated rats showed gradual increases in depression-like behavior over time, which were accompanied by similarly gradual decreases in reelin expression in the dentate subgranular zone and decreases in the number and dendritic complexity of surviving immature dentate granule cells. Interestingly, corticosterone had no significant effect on dendritic complexity in mature granule cells. These results support our hypothesis that reelin plays a role in the pathogenesis of depression and suggest that reelin could be an important target for the development of novel therapeutics for the treatment of depression.
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