Abstract
Testosterone produced by the foetal testis is converted by male neurons to oestradiol, which masculinizes neuronal morphology. Female neurons are known to synthesize oestradiol in absence of exogenous testosterone. However, the role of neuronal oestradiol on the differentiation of foetal female neurons is unknown. Here we show that, due to endogenous neuronal oestradiol synthesis, female hippocampal neurons have higher expression of the neuritogenic protein Neurogenin 3 and enhanced neuritogenesis than males. Exogenous application of testosterone or its metabolite dihydrotestosterone increases Neurogenin 3 expression and promotes neuritogenesis in males, but reduces these parameters in females. Together our data indicate that gonadal-independent oestradiol synthesis by female neurons participates in the generation of sex differences in hippocampal neuronal development.
Highlights
Previous studies have shown that oestradiol exogenously applied to hippocampal slice cultures had no effect on synapse density unless oestradiol synthesis was inhibited by using an aromatase inhibitor[15]. In view of this finding, we studied whether a similar mechanism underlies the failure of exogenous oestradiol to induce neuritogenesis in the cultures of female primary hippocampal neurons
The findings suggest that the negative regulation of neuritogenesis by testosterone in female neurons is mediated by DHT
We have identified Ngn[3] as a factor involved in neuritogenesis of both male and female neurons and we have shown that the sex difference in neuronal development was associated with a higher expression of Ngn[3] in female neurons than in male neurons during the first 2 DIV
Summary
Oestradiol treatment in the presence of letrozole increased the number of primary dendrites (Bonferroni p = 0.003), the axonal length (p < 0.001) and the number of intersections (p < 0.001) in female neurons compared to the cultures treated with letrozole alone but did not affect these parameters in male neurons (Fig. 7d). In female neurons, application of testosterone resulted in a decrease in Ngn[3] mRNA levels ( p = 0.011; Fig. 7c), in a significant increase in the proportion of cells in Stage I (p = 0.046; Fig. 10a,b) and in a significant decrease in the number of primary dendrites (p < 0.001), the length of axons (p < 0.001) and the number of intersections (p < 0.001) vs control values (Fig. 10f).
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