Dose-dependent regulation of steroid receptor coactivator-1 and steroid receptors by testosterone propionate in the hippocampus of adult male mice

Androgens have been proposed to play important roles in the regulation of hippocampus function either directly, through the androgen receptor (AR), or indirectly, through estrogen receptors (ERs), after aromatization into estradiol. Steroid receptor coactivator-1 (SRC-1) is present in the hippocampus of several species, and its expression is regulated by development and aging, as well as by orchidectomy and aromatase inhibitor letrozole administration, while ovariectomy only transiently downregulated hippocampal SRC-1. However, whether the expression of hippocampal SRC-1 can be directly regulated by testosterone, the principal male sex hormone, remains unclear. In the present study, we investigated the expression of hippocampal SRC-1 after orchidectomy and testosterone treatment using immunohistochemistry and Western blot analysis. We found that while hippocampal SRC-1 was significantly downregulated by orchidectomy (ORX), its expression was rescued by treatment with testosterone in a dose-dependent manner. Furthermore, we noticed that the decreased expression of hippocampal AR, ERs and the synaptic proteins GluR-1 and PSD-95 induced by ORX was also rescued by testosterone treatment in a dose-dependent manner. However, we found that hippocampal membrane estrogen receptor GPR30 and dendritic spine marker spinophilin were not altered by ORX or testosterone treatment. Together, the above results provided the first direct evidence for the androgenic regulation on hippocampal SRC-1, indicating that SRC-1 may be a direct target of androgenic regulation on the hippocampus. Furthermore, because AR and ERs can be differentially regulated by testosterone, and the transcriptional activity requires the involvement of local SRC-1, and considering the complicated regulatory pathway of each individual receptor, the converged hub regulator SRC-1 of these nuclear receptor networks is worthy of further investigation.