Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We believe we report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of Fragile X syndrome and describe potentially treatable underlying causes. The hippocampus is critical for the formation and use of episodes, with semantic (cue identity) information relayed to the structure via the lateral perforant path (LPP). The unusual form of synaptic plasticity expressed by the LPP (lppLTP) was profoundly impaired in Fmr1-KOs relative to wild-type mice. Two factors contributed to this defect: (i) reduced GluN1 subunit levels in synaptic NMDA receptors and related currents, and (ii) impaired retrograde synaptic signaling by the endocannabinoid 2-arachidonoylglycerol (2-AG). Studies using a novel serial cue paradigm showed that episodic encoding is dependent on both the LPP and the endocannabinoid receptor CB₁, and is strikingly impaired in Fmr1-KOs. Enhancing 2-AG signaling rescued both lppLTP and learning in the mutants. Thus, two consequences of the Fragile-X mutation converge on plasticity at one site in hippocampus to prevent encoding of a basic element of cognitive memory. Collectively, the results suggest a clinically plausible approach to treatment.

中文翻译：

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治疗新型可塑性缺陷可挽救脆弱X模型小鼠的发作性记忆。

情景记忆是人类认知的基本组成部分，在自闭症中会大大受损。我们相信我们在脆性X综合征的Fmr1-敲除（KO）小鼠模型中报告了此问题的第一个证据，并描述了可能的潜在潜在原因。海马对于发作的形成和使用至关重要，语义（提示同一性）信息通过横向穿孔路径（LPP）传递到结构中。由LPP（lppLTP）表达的异常形式的突触可塑性相对于野生型小鼠在Fmr1-KOs中受到了严重损害。导致该缺陷的因素有两个：（i）突触NMDA受体和相关电流中GluN1亚基水平的降低，以及（ii）内源性大麻素2-花生四烯酸甘油酯（2-AG）损害了逆行突触信号。₁，并且在Fmr1-KOs中显着受损。增强2-AG信号可以挽救突变体中的lppLTP和学习。因此，Fragile-X突变的两个后果是在海马体的一个部位聚集可塑性，以防止编码认知记忆的基本元素。总体而言，结果表明了一种临床上可行的治疗方法。