BDNF and Spine-Related Disorders of Memory and Cognition (P01).

总体方案摘要。形态异常的树突棘出现在各种形式的智力迟钝中，也出现在与记忆和认知障碍相关的精神疾病中。这些被广泛报道的观察结果提出了一种可能性，即脊柱肌动蛋白细胞骨架调节过程中的缺陷是一系列学习障碍的共同最终底物。目前的提案是ppg# P01NS045260的修订更新申请，解决了这一假设及其建议的潜在治疗策略。先前PPG奖下的工作表明，长期增强（LTP）的稳定性（一种与持久记忆编码密切相关的突触可塑性形式）在五种明显不同类型的记忆障碍（中年、早期亨廷顿病（HD）、脆性x综合征（FXS）、早期生活压力和更年期）的啮齿动物模型中受到中度至重度损伤。新引入的光学显微镜技术获得的证据表明，至少在这些病例中，ltp相关的脊柱细胞骨架重组有缺陷。脑源性神经营养因子（BDNF）的输注挽救了四个模型中的LTP，并恢复了两个模型中活性驱动的细胞骨架变化。增加脑内BDNF的浓度，使用作为先前PPG目标之一的每日药物治疗方案，也会产生类似的效果。拟议的研究有以下目标：i)测试活动驱动的细胞骨架重组在不同啮齿动物记忆障碍模型中异常的具体预测（这需要在先前工作中使用的小鼠模型中添加Angelman综合征的小鼠模型）；Ii)确定不同模型中导致细胞骨架缺陷的原因（酶、信号异常）；iii)测试慢性上调BDNF是否会增加突触中的BDNF信号传导并恢复脊髓中的肌动蛋白信号传导。将有四个子项目，由不同的pi指导：每个子项目都有自己的啮齿动物模型，并以细胞骨架信号传导的不同方面为重点。核心设施将构成第五个子项目，并将为该计划提供分析、管理和动物服务。总而言之，拟议的研究有望测试导致不同来源的突触可塑性和记忆障碍的常见神经生物学缺陷的存在，并评估临床相关的脊柱可塑性和行为正常化策略。

Overall Program Abstract. Dendritic spines with abnormal morphology occur in various forms of mental retardation and are also found in psychiatric conditions associated with disturbances to memory and cognition. These widely reported observations raise the possibility that defects in the processes that regulate the spine actin cytoskeleton are a common final substrate for a broad array of learning disabilities. The present proposal, which is a revised application for renewal of PPG #P01NS045260, addresses this hypothesis and potential therapeutic strategies suggested by it. Work under the previous PPG award showed that the stabilization of long-term potentiation (LTP), a form of synaptic plasticity closely related to the encoding of lasting memory, is moderately to severely impaired in rodent models of five distinctly different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), early-life stress, and menopause. Evidence obtained with newly introduced light microscopic techniques indicates that LTP-related reorganization of the spine cytoskeleton is defective in at least three of these cases. Infusions of Brain-Derived Neurotrophic Factor (BDNF) rescued LTP in four of the models and restored activity-driven changes to the cytoskeleton in two so far studied. Increasing brain concentrations of BDNF, using daily drug regimens developed as one of goals the previous PPG, produces similar effects. The proposed studies have the following objectives: i) test the specific prediction that activity-driven cytoskeletal reorganization is abnormal in the different rodent models of memory impairment (this entails adding a mouse model of Angelman's Syndrome to those used in previous work); ii) identify reasons (enzyme, signaling abnormalities) contributing to cytoskeletal defects in the different models; and iii) test if chronic up-regulation of BDNF increases BDNF signaling at synapses and restores actin signaling in spines. There will be four subprojects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. A Core facility will make up the fifth subproject and will provide analytical, administrative, and animal services for the program. In all, the proposed studies are expected to test for the presence of a common neurobiological defect contributing to synaptic plasticity and memory disorders of different origin and to evaluate a clinically relevant strategy for normalizing spine plasticity and behavior.