Loss and rescue of endocannabinoid-dependent LTP and memory in Fragile-X model mice

对系列事件的“什么”、“何时”和“在哪里”的记忆，被称为“情节记忆”，是记忆中的一个关键因素 人类认知，特别是在先天性智力残疾(ID)的情况下，包括 自闭症谱系障碍(ASDS)。情景式记忆的编码依赖于内嗅皮层 其中内侧(MEC)和侧向(LEC)场支持空间和非空间存储器的处理， 分别进行了分析。目的是了解自闭症中导致ID的神经生物学过程 对于先天性认知功能障碍和其他形式的疾病，我们已经评估了传播机制 脆性X在Fmr1 KO小鼠模型中向海马区LEC投射的持久突触可塑性 综合征(FXS)，最常见的ID遗传形式，也是自闭症的共病。我们的结果显示 Fmr1 KOS在LEC中长时程增强(LTP)的表达存在特别严重的缺陷。 海马连接(外侧穿支路径，LPP)和学习情节记忆任务失败，在野外 类型(WT)小鼠，取决于LPP。拟议的研究建立在这些结果的基础上，目标是确定 Fmr1 KO中LTP失败的潜在机制和测试预计将拯救两者的操作 增强和情景记忆。该项目利用了我们最近发现的LPP中的LTP 涉及新底物：LPP增强是在突触后诱导的，但在突触前表达，通过 增加递质释放，以内源性大麻素(ECB)2-花生四烯基甘油(2-AG)为关键 逆行信使。这种ECB依赖的LTP(EcLTP)背后的突触前调节涉及CB1 -LPP终端内介导的信号和细胞骨架重组。总体而言，这些结果表明 编码情节记忆依赖于突触可塑性的一种不寻常的、特定于路径的形式。三位一体 特定的目标将在Fmr1 KO小鼠身上测试这种ecLTP机制严重受损的假设， 因此(I)解释情节记忆的障碍和(Ii)确定改善的治疗目标 了解与自闭症相关的这种和其他形式的ID。目标1将识别突触后 Fmr1 KO中有缺陷的ecLTP所需的流程：此目标建立在初步结果的基础上 这表明在Fmr1 KO小鼠中2-AG的按需产生受到损害。目标2将测试突触前 调节ecLTP表达的事件在KOS中受损，特别是如果有 2-AG分解和CB1信号对肌动蛋白调节的干扰。最后，目标3将测试Fmr1中的IF Kos ecLTP和依赖于它的情节记忆可以通过增强2-AG的操作来挽救 级别。这些研究使用了一种新的学习范式来测试情景记忆的“什么”成分 其中WT学习依赖于LPP和Fmr1KO编码严重受损。总而言之，结果将是 对先天ID的情节记忆障碍的基础提供独特的见解并识别小说 治疗目标和候选治疗方法，用于增强认知的这一特定组成部分。

Memory for the ‘what’, when’ and ‘where’ of serial events, termed ‘episodic memory’, is a critical element in human cognition and is particularly disturbed in conditions of congenital intellectual disability (ID) including autism spectrum disorders (ASDs). The encoding of episodic-like memory depends upon the entorhinal cortex with medial (MEC) and lateral (LEC) fields supporting processing of spatial and non-spatial memories, respectively. With the goal of understanding the neurobiological processes contributing to ID in autism disorders and other forms of congenital cognitive dysfunction, we have evaluated mechanisms of transmission and enduring synaptic plasticity in LEC projections to hippocampus in the Fmr1 KO mouse model for Fragile-X Syndrome (FXS), the most common inherited form of ID which is also co-morbid for autism. Our results show that Fmr1 KOs have particularly severe deficits in the expression of Long-Term Potentiation (LTP) in the LEC- hippocampal connection (the lateral perforant path, LPP) and fail to learn episodic memory tasks that, in wild type (WT) mice, depend upon the LPP. Proposed studies build on these results with goals to identify mechanisms underlying the failure of LTP in Fmr1 KOs and to test manipulations predicted to rescue both potentiation and episodic memory. The project takes advantage of our recent discovery that LTP in the LPP involves novel substrates: LPP potentiation is induced postsynaptically but expressed presynaptically, via increased transmitter release, with the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) as the critical retrograde messenger. The presynaptic adjustments underlying this eCB-dependent LTP (ecLTP) involve CB1 –mediated signaling and cytoskeletal reorganization within LPP terminals. Collectively, the results suggest that encoding episodic memories depends upon an unusual, pathway specific-form of synaptic plasticity. The three specific aims will test the hypothesis that mechanisms of this ecLTP are severely impaired in Fmr1 KO mice, thus (i) accounting for disturbances in episodic memory and (ii) identifying therapeutic targets to improve learning in this and potentially other forms of ID associated with autism. Aim 1 will identify postsynaptic processes required for ecLTP that are defective in Fmr1 KOs: this aim builds upon preliminary results indicating that on-demand production of 2-AG is impaired in Fmr1 KO mice. Aim 2 will test if presynaptic events that regulate the expression of ecLTP are impaired in the KOs and, in particular, if there are disturbances in the regulation of 2-AG breakdown and CB1 signaling to actin. Finally, Aim 3 will test if in Fmr1 KOs ecLTP, and episodic memory that depends upon it, are rescued by manipulations that enhance 2-AG levels. These studies use a new learning paradigm that tests the `what' component of episodic memory for which WT learning depends on the LPP and Fmr1 KO encoding is severely impaired. Together, results will provide unique insights into the bases of disturbances in episodic memory with congenital ID and identify novel therapeutic targets, and candidate treatments, for enhancement of this specific component of cognition.