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：
9502329
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/9502329
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.

“什么”的记忆，当'''''''''where serial事件（称为“情节内存”）是关键元素人类认知，在先天性智力残疾（ID）的条件下特别受到干扰自闭症谱系障碍（ASDS）。情节状记忆的编码取决于内嗅皮层使用培养基（MEC）和横向（LEC）字段，支持处理空间和非空间记忆的处理，目的是了解有助于自闭症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，我们评估了传播的机制在LEC项目中持久的突触可塑性，用于fmr1 ko小鼠模型的海马模型综合征（FXS），这是自闭症的最常见的ID形式，也是自闭症的合并。我们的结果表明 FMR1 KO在LEC-的长期增强表达（LTP）方面具有特别严重的定义。海马连接（横向穿孔路径，LPP），无法学习情节记忆任务，这些任务在野外类型（WT）小鼠，取决于LPP。拟议的研究以这些结果为基础，其目标是确定 LTP在FMR1 KOS中失败的机制，并预测进行操作可以挽救两者增强和情节记忆。该项目利用了我们最近发现的LTP 涉及新颖的底物：LPP增强是突触后诱导的，但通过前突触诱导，通过发射器释放增加，内源性大麻素（ECB）2-芳基烯丙基甘油（2-AG）作为临界逆行使者。该依赖ECB的LTP（ECLTP）的突触前调整涉及CB1 - LPP末端内介导的信号传导和细胞骨架重组。总体上，结果表明编码发作的记忆取决于突触可塑性的异常，途径特异性。三个具体目的将检验以下假设：在FMR1 KO小鼠中，ECLTP的机制严重受损因此（i）考虑情节记忆中的灾难，以及（ii）识别治疗目标以改进学习与自闭症相关的此和潜在的其他形式的ID。 AIM 1将识别突触后的 FMR1 KOS中有缺陷的ECLTP所需的流程：此目标以初步结果为基础表明在FMR1 KO小鼠中，2AG的按需生产受损。 AIM 2将测试是否突触前调节ECLTP表达的事件在KOS中受到损害，尤其是对肌动蛋白的2-AG分解和CB1信号传导调节的干扰。最后，AIM 3将测试是否在FMR1中 KOS ECLTP和取决于它的情节记忆是通过增强2-ag的操作做出的水平。这些研究使用了一种新的学习范式，该范式测试了情节记忆的“什么”组成部分 WT学习取决于LPP和FMR1 KO编码受到严重损害。结果将在一起用先天性ID提供对情节记忆中灾难基础的独特见解并确定小说治疗靶标和候选治疗方法，以增强认知的这一特定组成部分。