Early life stress stimulates hippocampal reelin gene expression in a sex‐specific manner: Evidence for corticosterone‐mediated action

Abstract

ABSTRACT:Early life stress predisposes to the development of psychiatric disorders. In this context the hippocampal formation is of particular interest, because it is affected by stress on the structural and cognitive level. Since little is known how early life stress is translated on the molecular level, we mimicked early life stress in mouse models and analyzed 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 intergroup 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 question whether corticosterone mediates the stress-induced up-regulation of reelin gene expression, we used age-matched hippocampal slice cultures derived from male and female mouse pups. Quantitative determination of mRNA levels revealed that corticosterone treatment significantly 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. V V C 2010 Wiley-Liss, Inc.

Corticosterone Regulates the Expression of Neuropeptide Y and Reelin in MLO-Y4 Cells

“…3 and 4), which is partially consistent with previous reports (Gross et al, 2010;Kobold et al, 2002). A negative regulation of CORT on reelin has also been noticed in murine hippocampi (Lussier et al, 2009;2011).…”

“…CORT is a stress hormone and can mediate NPY and reelin production in the nervous system both in vivo and in vitro (Gross et al, 2010;Husum and Mathé, 2002). In the present study, the effectiveness of the CORT treatment in MLO-Y4 cells could be verified by the expression of DMP1, an ECM protein produced by osteocytes.…”

“…Increased serum corticosterone in mice or cortisol in humans can alter the expression of NPY and reelin in the nervous system (Akabayashi et al, 1994;Gross et al, 2010;Husum and Mathé, 2002;Lussier et al, 2011) and possibly in bone. Although the exact role of reelin still remains unclear, the significance of NPY in bone remodeling has been recognized.…”

Infant maternal separation impairs adult cognitive performance in BALB/cJ mice

“…Sex differences in the effects of IMS on hippocampal gene expression have also been reported. A modified IMS protocol in which pups are separated individually was reported to increase the expression of Reelin in male, but not female, mouse hippocampus (Gross et al 2010). Reelin expression regulates the development and differentiation of the hippocampus, is modulated by corticosterone, and could influence hippocampal dependent behaviors.…”

Revisiting hippocampal sclerosis in mesial temporal lobe epilepsy according to the “two-hit” hypothesis

“…For example, early life stress (maternal deprivation) or hypothyroidism increase methylation of reelin and BDNF DNAs [31,[40][41][42]44,46,[113][114][115] whereas valproate induced a demethylation of the DNA of reelin [48]. In KA-MTLE mice, BDNF expression was shown to be strongly increased with a time-course parallel to GCD [50][51][52][53]116,117].…”