RT Journal Article
SR Electronic
T1 ERα signaling is required for TrkB mediated hippocampal neuroprotection in female neonatal mice after hypoxic ischemic encephalopathy
JF eneuro
JO eneuro
FD Society for Neuroscience
SP ENEURO.0025-15.2015
DO 10.1523/ENEURO.0025-15.2015
A1 Ulas Cikla
A1 Vishal Chanana
A1 Douglas B. Kintner
A1 Eshwar Udho
A1 Jens Eickhoff
A1 Wendy Sun
A1 Stephanie Marquez
A1 Lucia Covert
A1 Arel Otles
A1 Robert A. Shapiro
A1 Peter Ferrazzano
A1 Raghu Vemuganti
A1 Jon E. Levine
A1 Pelin Cengiz
YR 2016
UL http://www.eneuro.org/content/early/2016/01/11/ENEURO.0025-15.2015.abstract
AB Male neonate brains are more susceptible to the effects of perinatal asphyxia resulting in hypoxia and ischemia (HI) related brain injury. The relative resistance of female neonatal brains to adverse consequences of HI suggests that there are sex-specific mechanisms that afford females greater neuroprotection and/or facilitates recovery post-HI. We hypothesized that HI preferentially induces estrogen receptor α (ERα) expression in female neonatal hippocampi and that ERα is coupled to Src family kinase (SFK) activation that in turn augments phosphorylation of the TrkB and thereby results in decreased apoptosis. After inducing the Vannucci’s HI model on P9 (C57BL/6J) mice, female and male ERα wild-type (ERα+/+) or ERα null mutant (ERα-/-) mice received vehicle control or the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF). Hippocampi were collected for analysis of mRNA of ERα and BDNF, protein levels of ERα, p-TrkB, p-src and cleaved caspase 3 (c-caspase-3) post-HI. Our results demonstrate that 1) HI differentially induces ERα expression in the hippocampus of the female vs. male neonate, 2) src and TrkB phosphorylation post-HI is greater in females than in males after 7,8-DHF therapy, 3) src and TrkB phosphorylation post-HI depend upon the presence of ERα, 4) TrkB agonist therapy decreases the c-caspase-3 only in ERα+/+ female mice hippocampus. Taken together, these observations provide evidence that female-specific induction of ERα expression confers neuroprotection with TrkB agonist therapy via SFK activation and account for improved functional outcomes in female neonates post-HI.Significance Statement: Female neonate brains are more resistant to the effects of hypoxia-ischemia (HI). We report a novel mechanism that involves the female-biased induction of ERα expression in the hippocampus post-HI, coupled to activation of a cytoplasmic kinase (src) and increased TrkB phosphorylation in the presence of a TrkB agonist. Thus, the enhanced TrkB receptor signaling resulting from this cross-talk mechanism confers decreased programmed cell death in response to TrkB agonist treatment in female versus male subjects. These results clearly demonstrate a role for ERα in enhancing TrkB activation and may account for the relative resistance of the female neonate brain to HI.