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Sex differences and estrogen regulation of BDNF gene expression, but not propeptide content, in the developing hippocampus.

ABSTRACT: Sex differences in adult brain function are frequently determined developmentally through the actions of steroid hormones during sensitive periods of prenatal and early postnatal life. In rodents, various cellular end points of the developing brain are affected by estradiol that is derived from the aromatization of circulating testosterone and/or synthesized within the brain. We have previously described a sex difference in neurogenesis in the hippocampus of neonatal rats that is modulated by estradiol. In this report, we examined a potential downstream regulator of the effects of estradiol on hippocampal cell proliferation by measuring gene expression of brain-derived neurotrophin (BDNF) in male and female neonatal rats in response to estradiol. Males had higher baseline BDNF gene expression in dentate gyrus and CA1 regions of the hippocampus compared with females. Neonatal administration of exogenous estradiol resulted in opposite effects on BDNF expression in these areas of the neonatal hippocampus, such that BDNF transcripts increased in CA1 but decreased in dentate. Blocking endogenous estradiol signaling by antagonizing estrogen receptors decreased BDNF expression in the dentate of males, but not females, and had no effect in CA1. Interestingly, this sex difference and response to estradiol was not mirrored by translational output, as no differences in BDNF precursor peptide were observed. The sex- and region-specific effects of estradiol on BDNF expression in the neonatal hippocampus suggest a complex functional relationship between these pleiotropic factors in regulating developmental neurogenesis. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Kight KE

PROVIDER: S-EPMC5120655 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Sex differences and estrogen regulation of BDNF gene expression, but not propeptide content, in the developing hippocampus.

Kight Katherine E KE McCarthy Margaret M MM

Journal of neuroscience research 20170101 1-2

Sex differences in adult brain function are frequently determined developmentally through the actions of steroid hormones during sensitive periods of prenatal and early postnatal life. In rodents, various cellular end points of the developing brain are affected by estradiol that is derived from the aromatization of circulating testosterone and/or synthesized within the brain. We have previously described a sex difference in neurogenesis in the hippocampus of neonatal rats that is modulated by es ...[more]

PMID: 27870444

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Project description:Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.

Dataset Information

Sex differences and estrogen regulation of BDNF gene expression, but not propeptide content, in the developing hippocampus.

Publications

Sex differences and estrogen regulation of BDNF gene expression, but not propeptide content, in the developing hippocampus.

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