Sex‐dependent alterations in BDNF‐TrkB signaling in the hippocampus of reelin heterozygous mice: a role for sex steroid hormones

Neurodevelopmental psychiatric disorders such as schizophrenia may be caused by a combination of gene × environment, gene × gene, and/or gene × sex interactions. Reduced expression of both Reelin and Brain‐Derived Neurotrophic factor (BDNF) has been associated with schizophrenia in human post‐mortem studies. However, it remains unclear how Reelin and BDNF interact (gene × gene) and whether this is sex‐specific (gene × sex). This study investigated BDNF‐TrkB signaling in the hippocampus of male and female Reelin heterozygous (Rln^+/?) mice. We found significantly increased levels of BDNF in the ventral hippocampus (VHP) of female, but not male Rln^+/? compared to wild‐type (WT) controls. While levels of TrkB were not significantly altered, phosphorylated TrkB (pTrkB) levels were significantly lower, again only in female Rln^+/? compared to WT. This translated to downstream effects with a significant decrease in phosphorylated ERK1 (pERK1). No changes in BDNF, TrkB, pTrkB or pERK1/2 were observed in the dorsal hippocampus of Rln^+/? mice. Ovariectomy (OVX) had no effect in WT controls, but caused a significant decrease in BDNF expression in the VHP of Rln^+/? mice to the levels of intact WT controls. The high expression of BDNF was restored in OVX Rln^+/? mice by 17β‐estradiol treatment, suggesting that Rln^+/? mice respond differently to an altered estradiol state than WT controls. In addition, while OVX had no significant effect on TrkB or ERK expression/phosphorylation, OVX + estradiol treatment markedly increased TrkB and ERK1 phosphorylation in Rln^+/? and, to a lesser extent in WT controls, compared to intact genotype‐matched controls. These data may provide a better understanding of the interaction of Reelin and BDNF in the hippocampus, which may be involved in schizophrenia.