Steroid hormones play important roles in brain development and function. The signaling of steroid hormones depends on the interaction between steroid receptors and their coactivators. Although the function of steroid receptor coactivators has been extensively studied in other tissues, their functions in the central nervous system are less well investigated. In this study, we addressed the function of steroid receptor coactivator 3 (SRC3) – a member of the p160 SRC protein family that is expressed predominantly in the hippocampus. While hippocampal development was not altered in Src3^+/− mice, hippocampus-dependent functions such as short-term memory and spatial memory were impaired. We further demonstrated that the deficient learning and memory in Src3^+/− mice was strongly associated with the impairment of long-term potentiation (LTP) at Schaffer Collateral-CA1 synapses. Mechanistic studies indicated that Src3^+/− mutation altered the composition of N-methyl-D-aspartate receptor subunits in the postsynaptic densities of hippocampal neurons. Finally, we showed that SRC3 regulated synaptic plasticity and learning mainly dependent on its lysine acetyltransferase activity. Taken together, these results reveal previously unknown functions of SRC3 in the hippocampus and thus may provide insight into how steroid hormones regulate brain function.

类固醇激素在大脑发育和功能中发挥重要作用。类固醇激素的信号传导取决于类固醇受体与其共激活剂之间的相互作用。尽管类固醇受体共激活剂的功能已在其他组织中得到广泛研究，但它们在中枢神经系统中的功能研究较少。在这项研究中，我们探讨了类固醇受体共激活因子 3 (SRC3) 的功能，它是主要在海马体中表达的 p160 SRC 蛋白家族的成员。虽然Src3 ^+/-小鼠的海马发育没有改变，但短期记忆和空间记忆等海马依赖性功能受损。我们进一步证明了Src3中的学习和记忆不足^+/-小鼠与 Schaffer Collat​​eral-CA1 突触的长期增强 (LTP) 损伤密切相关。机制研究表明，Src3 ^+/-突变改变了海马神经元突触后密度中 N-甲基-D-天冬氨酸受体亚基的组成。最后，我们发现 SRC3 调节突触可塑性和学习主要依赖于其赖氨酸乙酰转移酶活性。总之，这些结果揭示了 SRC3 在海马体中以前未知的功能，因此可以深入了解类固醇激素如何调节大脑功能。