Modulatory Effects of Sex Steroid Hormones on Brain‐Derived Neurotrophic Factor‐Tyrosine Kinase B Expression during Adolescent Development in C57Bl/6 Mice

Abstract

Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the adolescent brain and have been implicated in the pathogenesis of neurodevelopmental disorders, including mental illness. We aimed to determine the association between altered levels of sex steroid hormones during adolescent development and neurotrophic signalling in the C57Bl/6 mouse. We first performed a week by week analysis from pre-pubescence to adulthood in male and female C57Bl/6 mice, measuring serum levels of testosterone and oestradiol in conjunction with western blot analysis of neurotrophin expression in the forebrain and hippocampal regions. Second, we manipulated adolescent sex steroid hormone levels by gonadectomy and hormone replacement at the pre-pubescent age of 5 weeks. Young-adult forebrain and hippocampal neurotrophin expression was then determined. Male mice showed significant changes in brain-derived neurotrophic factor (BDNF) expression in the forebrain regions during weeks 7-10, which corresponded significantly with a surge in serum testosterone. Castration and testosterone or di-hydrotestosterone replacement experiments revealed an androgen receptor-dependent effect on BDNF-tyrosine kinase (Trk) B signalling in the forebrain and hippocampal regions during adolescence. Female mice showed changes in BDNF-TrkB signalling at a much earlier time point (weeks 4-8) in the forebrain and hippocampal regions and these did not correspond with changes in serum oestradiol. Ovariectomy actually increased BDNF expression but decreased TrkB phosphorylation in the forebrain regions. 17β-Oestradiol replacement had no effect, suggesting a role for other ovarian hormones in regulating BDNF-TrkB signalling in the adolescent female mouse brain. These results suggest the differential actions of sex steroid hormones in modulating BDNF-TrkB signalling during adolescence. These data provide insight into how the male and female brain changes in response to altered levels of circulating sex steroid hormones and could help to explain some of the developmental sex differences in the pathogenesis of neurodevelopmental disorders, including mental illness.

Parental brain‐derived neurotrophic factor genotype, child prosociality, and their interaction as predictors of parents’ warmth

“…Various studies in mice (Advani et al., 2009; Ren‐Patterson et al., 2006) and in humans (Shalev et al., 2009; Verhagen et al., 2010) have shown a sex difference in the effect of BDNF. This difference may be related to the interactions between BDNF and sex hormones such as estradiol (Begliuomini et al., 2007; Sohrabji et al., 1995) and testosterone (Hill et al., 2012; Verhovshek et al., 2010). Another explanation for the sex difference in the interaction effect might lie in the lower variability found for maternal warmth compared to paternal warmth.…”

“…In humans, the val66met polymorphism of the BDNF gene affects the onset of multiple sclerosis (MS) only in men and increases the risk of MS only in women (Mirowska‐Guzel, Mach, Gromadzka, Czlonkowski, & Czlonkowska, 2008). These differences may be explained by interactions between BDNF and sex hormones such as estradiol (Begliuomini et al., 2007; Sohrabji, Miranda, & Toran‐Allerand, 1995) and testosterone (Hill, Wu, Kwek, & van den Buuse, 2012; Verhovshek, Cai, Osborne, & Sengelaub, 2010). In rats, estrogen has been shown to regulate BDNF mRNA levels, possibly via an estrogen response element on the BDNF gene (Sohrabji et al., 1995).…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…This may be due to sex-specific developmental expression profiles of these genes, or sex steroid hormone influences (Wong et al 2009;Hill 2012a;Hill et al 2012b;Hill et al 2013). Indeed, recent work from our laboratory demonstrate that M a n u s c r i p t 29 estradiol regulates the expression of parvalbumin positive interneurons during adolescence in the dorsal hippocampus and maintains spatial memory in WT but not BDNF heterozygous ovariectomized mice, suggesting a role for BDNF in mediating the cognitive enhancing effects of estradiol (Wu et al 2015).…”

The different effects of maternal separation on spatial learning and reversal learning in rats

“…And there is no significant sex and age difference in the spatial learning test. However, Hill et al found that male rats showed disruptions in spatial memory (Y-maze), induced by MS, which were absent in females [42], and this may be due to the different effects of sex steroid hormones on BDNF-TrkB signaling [43]. The discrepancies may be due to differences in experimental design, strain differences, the control group examined, or all of these factors.…”