BDNF and Spine-Realted Disorders of Memory and Cognition

描述(申请人提供)：记忆和认知障碍与异常树突棘和/或调节脊椎肌动蛋白细胞骨架的信号障碍有关。补充结果表明，长时程增强(LTP)是一种突触可塑性形式，被认为是记忆编码的基础，需要脊柱肌动蛋白重塑。这些观察结果表明，在各种情况下，LTP巩固的细胞骨架机制中的缺陷代表了记忆障碍的共同神经生物学基础，以及改善认知能力的治疗目标。目前关于延长#P01NS045260资金的提议解决了这一假设。程序研究表明，在六种不同类型的记忆障碍的啮齿动物模型中，LTP的稳定性受到损害：中老年、早期亨廷顿病(HD)、脆性X综合征(FXS)、Angelman综合征、短期应激和低雌激素水平。在到目前为止测试的每个实例中，LTP相关的脊柱细胞骨架重组是有缺陷的，注射和/或上调脑源性神经营养因子(BDNF)可以挽救LTP和细胞骨架的变化。此外，活动驱动的肌动蛋白重塑被证明涉及介导脊柱F-肌动蛋白组装和稳定的不同级联，这在动物模型中受到不同程度的损害，但两者都受到BDNF的促进。拟议的研究以这些发现为基础：i)确定在七种截然不同的记忆障碍啮齿动物模型中，与LTP相关的活动驱动的肌动蛋白信号传导的缺陷；ii)确定行为诱导的肌动蛋白信号和学习是否在啮齿动物模型中受损；iii)测试BDNF蛋白含量的慢性上调是否增加了通过BDNF的TrkB受体和肌动蛋白调节级联反应的信号，如在体外和体内评估的那样；以及iv)测试后一种影响伴随着每种啮齿动物模型中行为异常的减少的预测。将有四个项目，由不同的PI指导：每个项目都有自己的啮齿动物模型，并以细胞骨架信号的不同方面为重点。核心A将为显微镜、电生理学、行为研究和所有项目使用的精选神经化学分析提供分析设施，并将支持行政和动物/试剂功能。总而言之，拟议的研究有望测试记忆障碍中是否存在最终的常见缺陷，并彻底评估使突触可塑性和行为正常化的临床相关策略。

DESCRIPTION (provided by applicant): Memory and cognitive disorders are associated with abnormal dendritic spines and/or disturbances to signaling regulating the spine actin cytoskeleton. Complementary results show that long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory encoding, requires spine actin remodeling. These observations suggest the hypothesis that defects in the cytoskeletal mechanisms of LTP consolidation represent a shared neurobiological basis for memory disturbances, and a therapeutic target for improving cognitive performance, in a variety of conditions. The present proposal for renewal of #P01NS045260 funding, addresses this hypothesis. Program studies have shown that LTP stabilization is impaired in rodent models of six different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), Angelman Syndrome, short-term stress, and low estrogen levels. In each instance thus far tested, LTP-related reorganization of the spine cytoskeleton was defective and infusions and/or upregulating Brain-Derived Neurotrophic Factor (BDNF) rescued LTP and cytoskeletal changes. Moreover, activity-driven actin remodeling was shown to involve distinct cascades mediating spine F-actin assembly and stabilization, that are differentially impaired across the animal models, but both facilitated by BDNF. The proposed studies build on these findings to: i) identify defects in activity-driven signaling to actin, associated with LTP, in seven distinctly different rodent models of memory impairment; ii) determine if behaviorally induced actin signaling and learning is impaired in the rodent models; iii) test if chronic up-regulation of BDNF protein content increases signaling through BDNF's TrkB receptor and actin regulatory cascades as assessed in vitro and in vivo; and iv) test the prediction that the latter effects are accompanied by a reduction in behavioral abnormalities in each of the rodent models. There will be four Projects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. Core A will provide analytical facilities for microscopy, electrophysiology, behavioral studies, and select neurochemical assays employed by all projects, and will support Administrative and Animal/Reagent functions. In all, the proposed studies are expected to test for the presence of a final, common defect in memory disorders and to thoroughly evaluate a clinically relevant strategy for normalizing synaptic plasticity and behavior.