Early Life Stress Stimulates Hippocampal Reelin Gene Expression in a Sex-Specific Manner: Evidence for Corticosterone-Mediated Action

ABSTRACT: Early life stress predisposes to the development of psychi-atric disorders. In this context the hippocampal formation is of particu-lar interest, because it is affected by stress on the structural and cogni-tive level. Since little is known how early life stress is translated on the molecular level, we mimicked early life stress in mouse models and ana-lyzed the expression of the glycoprotein Reelin, a master molecule for development and differentiation of the hippocampus. From postnatal day 1 (P1) to P14, mouse pups were subjected to one of the following treatments: nonhandling (NH), handling (H), maternal separation (MS), and early deprivation (ED) followed by immediate (P15) or delayed (P70) real time RT-PCR analysis of reelin mRNA expression. We show that at P15, reelin mRNA levels were significantly increased in male H and ED groups when compared with the NH group. In contrast, no stress-induced alterations of reelin mRNA expression were found in female animals. This sex difference in stress-mediated stimulation of reelin expression was maintained into adulthood, since at P70 inter-group differences were still found in male, but not in female mice. On the cellular level, however, we did not find any significant differences in cell densities of Reelin-immunolabeled neurons between treatment groups or sexes, but an overall reduction of Reelin-expressing neurons in the adult hippocampus when compared to P15. To address the ques-tion whether corticosterone mediates the stress-induced up-regulation of reelin gene expression, we used age-matched hippocampal slice cul-tures derived from male and female mouse pups. Quantitative determi-nation of mRNA levels revealed that corticosterone treatment signifi-cantly up-regulated reelin mRNA expression in male, but not in female hippocampi. Taken together, these results show a sex-specific regulation of reelin gene expression by early life experience, most likely mediated by corticosterone. VC 2010 Wiley Periodicals, Inc