Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect synaptic function and cognition in an androgen receptor (AR)-independent manner; however, the mechanisms connecting theses effects are unknown. Therefore, we used testicular feminization mutation (Tfm) male mice, a model with AR mutation, to test the effects of testosterone on synaptic function and cognition. Our results showed that testosterone ameliorated spatial memory deficit and neuronal damage, and increased dendritic spines density and postsynaptic density protein 95 (PSD95) and glutamate receptor 1 (GluA1) expression in the hippocampus of Tfm male mice. And these effects of testosterone were not inhibited by anastrozole, which suppressed conversion of testosterone to estradiol. Mechanistically, testosterone activated the extracellular signal-related kinase 1/2 (Erk1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) in the hippocampus of Tfm male mice. Meanwhile, Erk1/2 inhibitor SCH772984 blocked the upregulation of phospho-CREB, PSD95, and GluA1 induced by testosterone in HT22 cells pretreated with flutamide, an androgen antagonist. Collectively, our data indicate that testosterone may ameliorate hippocampal synaptic damage and spatial memory deficit by activating the Erk1/2–CREB signaling pathway in an AR-independent manner.

与衰老相关的雄激素水平降低可能是神经退行性疾病的一个可能的危险因素，并导致认知障碍。雄激素可能以不依赖于雄激素受体（AR）的方式影响突触功能和认知；然而，连接这些效应的机制尚不清楚。因此，我们使用睾丸女性化突变（Tfm）雄性小鼠（一种带有AR突变的模型）来测试睾酮对突触功能和认知的影响。我们的结果表明，睾酮可改善 Tfm 雄性小鼠海马的空间记忆缺陷和神经元损伤，并增加树突棘密度和突触后密度蛋白 95 (PSD95) 和谷氨酸受体 1 (GluA1) 的表达。阿那曲唑不会抑制睾酮的这些作用，阿那曲唑会抑制睾酮向雌二醇的转化。从机制上讲，睾酮激活Tfm雄性小鼠海马中的细胞外信号相关激酶 1/2 (Erk1/2) 和环磷酸腺苷反应元件结合蛋白 (CREB) 。同时，在用雄激素拮抗剂氟他胺预处理的 HT22 细胞中，Erk1/2 抑制剂 SCH772984 阻断了睾酮诱导的磷酸-CREB、PSD95 和 GluA1 的上调。总的来说，我们的数据表明睾酮可能通过以 AR 独立的方式激活 Erk1/2-CREB ​​信号通路来改善海马突触损伤和空间记忆缺陷。