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

Fragile-X 模型小鼠内源性大麻素依赖性 LTP 和记忆的丧失与挽救

基本信息

批准号：
9332463
负责人：
Christine M Gall
金额：
$ 42.67万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332463
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling Accounting Actins Autistic Disorder Behavior CNR1 gene Chemosensitization Cognition Comorbidity Cytoskeletal Modeling Cytoskeleton Disease Electrophysiology (science)Elements Endocannabinoids Enzymes Episodic memory Event FMR1 Failure Focal Adhesion Kinase 1 Fragile X Syndrome Glutamate Receptor Goals Hippocampus (Brain)Human Hydrolase Impaired cognition Impairment In Vitro Inherited Integrins Intellectual functioning disability Knock-out Knockout Mice Lateral Learning Link Long-Term Potentiation Medial Mediating Memory Monoacylglycerol Lipases N-Methylaspartate Neurobiology Neurons Pathway interactions Perforant Pathway Phenotype Phosphotransferases Population Process Production Proteins Receptor Activation Regulation Rodent Series Signal Transduction Site Source Synapses Synaptic Transmission Synaptic plasticity System Testing Vertebral column Wild Type Mouse Work autism spectrum disorder base behavioral outcome cholinergic cognitive function dentate gyrus design endocannabinoid signaling entorhinal cortex episodic like memory episodic memory impairment experience experimental study improved in vivo insight lipoprotein lipase mouse model neurochemistry new therapeutic target novel postsynaptic presynaptic therapeutic target transmission process treatment effect

项目摘要

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.

对连续事件的“内容”、“时间”和“地点”的记忆，称为“情景记忆”，是人类认知，特别是在先天性智力障碍（ID）的情况下受到干扰，包括自闭症谱系障碍 (ASD) 情景记忆的编码取决于内嗅皮层。具有支持空间和非空间记忆处理的内侧（MEC）和外侧（LEC）场，分别是为了了解导致自闭症 ID 的神经生物学过程。疾病和其他形式的先天性认知功能障碍，我们评估了传播机制 Fragile-X 的 Fmr1 KO 小鼠模型中 LEC 投射到海马体的持久突触可塑性综合症（FXS）是最常见的智力障碍遗传形式，我们的研究结果显示，它也是自闭症的共病。 Fmr1 KOs 在 LEC 中的长时程增强 (LTP) 表达方面具有特别严重的缺陷海马连接（横向穿通路径，LPP）并且无法学习情景记忆任务，这些任务在野外型（WT）小鼠，取决于 LPP 所提议的研究以这些结果为基础，其目标是确定。 Fmr1 KO 中 LTP 失败的潜在机制，并测试预测可挽救两者的操作该项目利用了我们最近发现 LPP 中的 LTP。涉及新的底物：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，其中内源性大麻素 (eCB) 2-花生四烯酰甘油 (2-AG) 是关键这种 eCB 依赖性 LTP (ecLTP) 的突触前调节涉及 CB1。 – LPP 终端内介导的信号传导和细胞骨架重组。情景记忆的编码取决于突触可塑性的不寻常的、途径特定形式。具体目标将测试这一假设：该 ecLTP 机制在 Fmr1 KO 小鼠中严重受损，因此（i）解释情景记忆的紊乱，以及（ii）确定改善的治疗目标学习这种与自闭症相关的潜在的智力障碍，目标 1 将识别突触后。 Fmr1 KO 中存在缺陷的 ecLTP 所需流程：这一目标建立在初步结果的基础上表明 Fmr1 KO 小鼠中 2-AG 的按需生成受到损害，Aim 2 将测试突触前是否存在。调节 ecLTP 表达的事件在 KO 中受到损害，特别是如果存在 2-AG 分解和 CB1 肌动蛋白信号传导的调节受到干扰最后，目标 3 将测试 Fmr1 中是否存在。通过增强 2-AG 的操作可以挽救 ecLTP 以及依赖于它的情景记忆这些研究使用了一种新的学习范式来测试情景记忆的“内容”成分。 WT 学习依赖于 LPP 和 Fmr1 KO 编码，两者结合起来，结果将受到严重损害。通过先天性 ID 和新颖的识别，为情景记忆障碍的基础提供独特的见解治疗目标和候选治疗，以增强认知的这一特定组成部分。