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

• 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
• 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

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.

对一系列事件的“什么”、“何时”和“何地”的记忆，被称为“情景记忆”，是记忆的一个关键因素。 人类认知，尤其是在先天性智力残疾（ID）的情况下， 自闭症谱系障碍（ASD）。情景记忆的编码依赖于内嗅皮层 利用支持空间和非空间记忆处理的内侧（MEC）和外侧（LEC）场， 分别目的是了解导致自闭症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，我们已经评估了传播机制， 在Fragile-X基因敲除小鼠模型中LEC向海马投射的持久突触可塑性 综合征（FXS），最常见的遗传形式的ID，也是自闭症的共同病态。我们的研究结果表明 Fmr 1科斯在LEC中的长时程增强（LTP）表达中具有特别严重的缺陷， 海马连接（横向穿孔路径，LPP）和无法学习情景记忆任务，在野生 型（WT）小鼠，取决于LPP。拟议的研究以这些结果为基础，并确定目标 潜在的FMR 1科斯LTP失败的机制，并测试预测拯救两者的操作 增强和情景记忆。该项目利用了我们最近发现的LPP中的LTP 涉及新的底物：LPP增强是在突触后诱导的，但在突触前表达， 增加递质释放，内源性大麻素（eCB）2-花生四烯酸甘油（2-AG）是关键 逆行信使这种依赖于eCB的LTP（ecLTP）的突触前调节涉及CB 1 - 介导的信号传导和LPP末端内的细胞骨架重组。总的来说，结果表明， 编码情景记忆依赖于突触可塑性的不寻常的、通路特异性形式。三 具体的目的将检验这一假设，即这种ecLTP的机制在Fmr 1 KO小鼠中严重受损， 因此（i）解释情景记忆中的干扰和（ii）确定治疗靶点以改善 在这种和其他可能与自闭症相关的ID形式中学习。Aim 1将识别突触后 在Fmr 1科斯中存在缺陷的ecLTP所需工艺：该目标建立在初步结果的基础上 表明在Fmr 1 KO小鼠中2-AG的按需产生受损。目标2将测试突触前 调节ecLTP表达的事件在科斯中受损，特别是，如果存在 2-AG分解和CB 1信号转导到肌动蛋白的调节紊乱。最后，目标3将测试是否在Fmr 1中 科斯的ecLTP和依赖于它的情景记忆可以通过增强2-AG的操作来拯救 程度.这些研究使用了一种新的学习范式，测试情景记忆中的“什么”成分， WT学习依赖于LPP，并且Fmr 1 KO编码严重受损。共同努力， 提供独特的见解，在情节记忆障碍的基础上与先天性ID和识别新的 治疗目标和候选治疗，以增强这一特定的认知成分。