Chronic stress contributes to numerous human pathologies including cognition impairments and psychiatric disorders. Glucocorticoids are primary stress hormones that activate two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR), that are both highly expressed in the hippocampus. To investigate potential combinatorial actions of hippocampal GR and MR, we developed mice with conditional knockout of both GR and MR in the hippocampus and compared them to their single knockout counterparts. Mice lacking MR alone or both GR and MR in the hippocampus exhibited altered expression of multiple CA2-specific neuronal markers and enhanced cue-dependent learning in a conditioned fear test. Provocatively, in contrast to the single knockouts, mice depleted of both GR and MR showed profound neurodegeneration of the hippocampus. Neuronal death was increased and neurogenesis was reduced in the dentate gyrus of the double knockout mice. Global gene expression assays of the knockout mice revealed a synergistic increase in the number of dysregulated genes in the hippocampus lacking both GR and MR. This large cohort of genes reliant on both GR and MR for expression was strongly associated with cell death and cell proliferation pathways. GR/MR complexes were detected in CA1 and dentate gyrus neurons suggesting receptor heterodimers contribute to the joint actions of GR and MR. These findings reveal an obligate role for MR signaling in regulating the molecular phenotype of CA2 neurons and demonstrate that combinatorial actions of GR and MR are essential for preserving dentate gyrus neurons and maintaining hippocampal health.

慢性压力会导致许多人类疾病，包括认知障碍和精神障碍。糖皮质激素是主要的应激激素，可激活两种密切相关的核受体，即糖皮质激素 (GR) 和盐皮质激素受体 (MR)，它们均在海马体中高度表达。为了研究海马 GR 和 MR 的潜在组合作用，我们开发了在海马中条件性敲除 GR 和 MR 的小鼠，并将它们与单个敲除的对应物进行了比较。海马体中缺乏 MR 或 GR 和 MR 的小鼠在条件恐惧测试中表现出多种 CA2 特异性神经元标记的表达改变和增强的线索依赖性学习。挑衅性地，与单次淘汰赛相比，耗尽 GR 和 MR 的小鼠表现出海马体的严重神经变性。双基因敲除小鼠齿状回的神经元死亡增加，神经发生减少。敲除小鼠的全局基因表达分析显示，缺乏 GR 和 MR 的海马中失调基因的数量协同增加。依赖 GR 和 MR 表达的大量基因与细胞死亡和细胞增殖途径密切相关。在 CA1 和齿状回神经元中检测到 GR/MR 复合物，表明受体异二聚体有助于 GR 和 MR 的联合作用。