NMDA receptor (NMDAR)-mediated calcium influx triggers the induction and initial expression of long-term potentiation (LTP). Here we report that in male rodents, ion flux-independent (metabotropic) NMDAR signaling is critical for a third step in the production of enduring LTP, i.e., cytoskeletal changes that stabilize the activity-induced synaptic modifications. Surprisingly, females rely upon estrogen receptor alpha (ERα) for the metabotropic NMDAR operations used by males. Blocking NMDAR channels with MK-801 eliminated LTP expression in hippocampal field CA1 of both sexes but left intact theta burst stimulation (TBS)-induced actin polymerization within dendritic spines. A selective antagonist (Ro25-6981) of the NMDAR GluN2B subunit had minimal effects on synaptic responses but blocked actin polymerization and LTP consolidation in males only. Conversely, an ERα antagonist thoroughly disrupted TBS-induced actin polymerization and LTP in females while having no evident effect in males. In an episodic memory paradigm, Ro25-6981 prevented acquisition of spatial locations by males but not females, whereas an ERα antagonist blocked acquisition in females but not males. Sex differences in LTP consolidation were accompanied by pronounced differences in episodic memory in tasks involving minimal (for learning) cue sampling. Males did better on acquisition of spatial information whereas females had much higher scores than males on tests for acquisition of the identity of cues (episodic "what") and the order in which the cues were sampled (episodic "when"). We propose that sex differences in synaptic processes used to stabilize LTP result in differential encoding of the basic elements of episodic memory.

NMDA 受体 （NMDAR） 介导的钙内流触发长时程增强 （LTP） 的诱导和初始表达。在这里，我们报道了在雄性啮齿动物中，离子通量非依赖性（代谢性）NMDAR 信号转导对于产生持久 LTP 的第三步至关重要，即稳定活性诱导的突触修饰的细胞骨架变化。令人惊讶的是，女性依赖雌激素受体 α （ERα） 进行雄性使用的代谢型 NMDAR 手术。用 MK-801 阻断 NMDAR 通道消除了两性海马场 CA1 中 LTP 的表达，但在树突棘内留下完整的 θ 爆发刺激 （TBS） 诱导的肌动蛋白聚合。NMDAR GluN2B 亚基的选择性拮抗剂 （Ro25-6981） 对突触反应的影响最小，但仅在男性中阻断肌动蛋白聚合和 LTP 巩固。相反，ERα 拮抗剂彻底破坏了 TBS 诱导的雌性肌动蛋白聚合和 LTP，而对雄性没有明显影响。在情景记忆范式中，Ro25-6981 阻止男性但不阻止女性获得空间位置，而 ERα 拮抗剂阻止女性但不阻止男性获得空间位置。LTP 巩固的性别差异伴随着涉及最小 （用于学习） 线索采样的任务中情景记忆的显着差异。男性在获取空间信息方面表现更好，而女性在获得线索身份（情景 “什么”）和线索采样顺序 （情景 “何时”） 的测试中得分远高于男性。我们提出，用于稳定 LTP 的突触过程的性别差异导致情景记忆基本元素的差异编码。