The Spine Cytoskeleton and Memory Disorders

本项目的长期目标是：（i）识别突触下细胞骨架的缺陷， 在记忆/认知障碍的啮齿动物模型中LTP巩固失败，以及（ii）使用该信息 开发新的，临床上合理的策略来抵消这些缺陷。在PPG的工作导致了一个模型， 涉及三类共同调节双肌动蛋白信号传导的膜受体的整合 组装和稳定肌动蛋白丝的途径。我们的研究表明，离散误差是 存在于这个复杂的系统中，在三个明显不同的啮齿动物模型中， 记忆问题。我们还发现，一种可释放的调节剂（脑源性神经营养因子： 当直接应用于脑切片或上调时，LTP模型中的BDNF）抵消了突触可塑性的缺陷 被毒品拟议的实验将采用一种新开发的方法， BDNF信号在突触中的传递，使关键的平移步骤的信号失败的分析 和潜在的治疗行为的动物，并分析信号缺陷如何影响区域分布 （"地图"）LTP相关的突触变化在学习过程中。

The long-term objectives of this project are to (i) identify defects in the subsynaptic cytoskeleton related to the failure of LTP consolidation in rodent models of memory/cognitive impairments and (ii) use this information to develop novel, clinically plausible strategies for counteracting the defects. Work in the PPG led to a model of consolidation involving three classes of membrane receptors that collectively regulate dual actin signaling pathways for assembling and stabilizing actin filaments. Our studies then showed that discrete errors are present in this complex system in three distinctly different rodent models of human conditions associated with memory problems. We also found that one of the releasable modifiers (Brain-Derived Neurotrophic Factor: BDNF) in the LTP model offsets defects in synaptic plasticity when applied directly to brain slices or when upregulated by drugs. The proposed experiments will employ a newly developed method that acutely, facilitates BDNF signaling at synapses, make the critical translational step of moving the analysis of signaling failures and potential therapies to behaving animals, and analyze how signaling defects affect the regional distribution ('maps') of LTP-related synaptic changes during learning.