17β-estradiol activation of dorsal hippocampal TrkB is independent of increased mature BDNF expression and is required for enhanced memory consolidation in female mice.

The potent estrogen 17β-estradiol (E) is known to enhance hippocampal memory and plasticity, however the molecular mechanisms underlying these effects remain unclear. Brain derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) are regulated by E, but the potential mechanistic roles of neurotrophic signaling in E-induced enhancement of memory are not well understood. Here, we examined the effects of hippocampal TrkB signaling on E-induced enhancement of memory consolidation in the object placement and recognition tasks. Bilateral infusion of the TrkB antagonist ANA-12 into the dorsal hippocampus of ovariectomized female mice blocked E-induced enhancement of memory consolidation, supporting a role for TrkB-mediated signaling in estrogenic regulation of memory. Although dorsal hippocampal E infusion increased levels of phospho-TrkB and mature BDNF (mBDNF) in the dorsal hippocampus within 4-6 h, E-induced increases in hippocampal mBDNF expression were not required for hippocampal TrkB activation and were not inhibited by TrkB antagonism. Thus, E regulates TrkB signaling to facilitate memory consolidation in a manner independent of mBDNF expression. Together these results provide the first direct evidence that E modulation of hippocampal TrkB signaling is required for its beneficial effects on memory consolidation and provide additional characterization of the ways in which TrkB/BDNF signaling is regulated by E in the hippocampus.