Orchiectomy and letrozole differentially regulate synaptic plasticity and spatial memory in a manner that is mediated by SRC-1 in the hippocampus of male mice.

Hippocampal synaptic plasticity is the basis of spatial memory and cognition and is strongly regulated by both testicular androgens (testosterone, T) and hippocampal estrogens (17β-estradiol, E2) converted from T by aromatase, which is inhibited by letrozole (LET), but the contribution of each pathway to spatial memory and the associated mechanisms are unclear. In this study, we first used orchiectomy (ORX) and LET injection to investigate the effects of T and hippocampal E2 on spatial memory and hippocampal synaptic plasticity. Next, we examined the changes in steroid receptors and steroid receptor coactivator-1 (SRC-1) under these treatments. Finally, we constructed an SRC-1 RNA interference lentivirus and an AROM overexpression lentivirus to explore the roles of SRC-1 under T replacement and AROM overexpression. The results revealed spatial memory impairment only after LET. LET induced more actin depolymerization and greater losses of spines, synapses, and postsynaptic proteins compared with ORX. Moreover, although ERα and ERβ were affected by LET and ORX at similar levels, AR, GPR30, and SRC-1 were dramatically decreased by LET compared with ORX. Finally, the T and AROM overexpression-induced changes in synaptic proteins and actin polymerization were blocked by SRC-1 inhibition. These results demonstrate that testicular androgens play a limited role, whereas local E2 is more important for cognition, which may explain why castrated men such as eunuchs usually do not have cognitive disorders. These results also suggest a pivotal role of SRC-1 in the action of steroids; thus, SRC-1 may serve as a novel therapeutic target for cognitive disorders.