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Commentary :
Introduction. Neuroestrogens are involved in many functions such as reproduction, cognition or neuroprotection. Once synthesized in the brain, they act on either nuclear or membrane receptors to regulate brain function in different time scales. While the transcriptional actions of liganded nuclear receptors usually results in physiological and behavioral effects within hours to days, the activation of intracellular signaling pathways by membrane receptors leads to more rapid (seconds/minutes) actions. Studies in several species have described rapid effects of estrogens on reproductive behavior [1]. These effects are observed within a few minutes, raising the hypothesis that they are related to membrane-initiated actions of estrogens. Experiments performed in Japanese quail demonstrated that brain derived estrogens control within minutes measures of male sexual motivation but not performance [2]. This work thus suggested that sexual motivation and performance might be differentially controlled by membrane versus nuclear estrogen receptor (mER vs nER) respectively [3,4].
In rodents, a few studies have characterized rapid effects of estrogens on sexual behavior [5,6]. In mice, estrogen receptor alpha (ERα) has been shown to play a major role in the control of male sexual behavior [7]. However, whether the translocation of this receptor and its activation at the membrane could rapidly affect male sexual behavior in rodents remains unclear. Recently, a mutant line carrying a mutated ERα unable to traffic to and signal from the membrane (C451A-ERα) was generated [8]. Moreover, estetrol (E4), a natural estrogen produced by human fetal liver, has been described to act as an agonist of nuclear estrogen receptors but as an antagonist on their membrane-associated fraction [9].
In the present study, we took advantage of the complementary properties of estetrol and C451A-ERα mice to investigate the role of membrane estrogen receptor alpha (mERα) in the motivational and copulatory aspects of male sexual behavior.
Methods. Sexually experienced and gonadally intact C451A-ERα and wild-type male mice were tested for sexual motivation with the partner preference test and for sexual performance by measuring the frequencies and latencies of anogenital investigations, mounts, intromissions and ejaculations observed during a 30 minutes interaction with an estrous female. Both aspects of behavior were tested 10 minutes after single subcutaneous injections of estetrol (E4, 3mg/Kg) or the aromatase inhibitor 1,4,6-Androstatriene-3,17-dione (ATD, 4mg/subject).
Results. Our results show that in wild-type males an acute treatment with ATD decreased both sexual performance, i.e. mount and intromission frequencies and sexual motivation, as the time spent by males in close proximity to the estrous female was decreased with ATD regardless of their genotype. These effects are not prevented by the mutation of ERα. On the contrary, in wild-type males, E4 rapidly decreased sexual performance but had no effect on the time spent near the female. The effect of E4 on sexual performance was prevented in C451A-ERα mice, thus indicating that it relied on mERα.
Conclusion. Together, these data confirmed previous results showing the key role of aromatization in the rapid control of male sexual performance [5] and extended this conclusion to sexual motivation suggesting that, as in quail, neuroestrogens rapidly affect male sexual motivation in mice. Moreover, they indicate that E4 rapidly inhibit the sexual performance, but not sexual motivation. This rapid inhibition of male copulatory behavior by E4 being prevented in mice invalidated for mERα further demonstrates the role of mERα in the regulation of rapid effects of neuroestrogens on sexual performance. Finally, the persistence of the effect of ATD on behavior in C451A-ERα mice suggests that another estrogen receptor, such as GPER1, could also regulate both aspects of male sexual behavior.
Acknowledgements:
This work was supported by FNRS Research Grant T.0042.15. CdB is a FNRS-F.R.S. Post-doctoral fellow. CAC is a FNRS-F.R.S Senior research associate.
