Kalirin Signaling in Spine Morphogenesis and Cognition in Vivo

描述（由申请人提供）：树突棘是大脑中大多数兴奋性突触的部位。脊柱密度和形态学的改变对学习记忆的形成具有重要意义，而脊柱功能障碍是阿尔茨海默病（AD）发病机制中的早期事件，可能直接导致认知功能障碍。Rho GEF kalirin已被证明通过其激活小GTCRac来控制树突棘形态发生。Rac反过来激活p21激活的激酶Pak，Pak反过来介导肌动蛋白细胞骨架重排和随后的棘形态变化。最近开发的第一只kalirin KO小鼠将用于确定先前表征的kalirin- Rac和kalirin-GluR 1体外相互作用是否在kalirin KO动物体内失调。此外，我们将表征kalirin KO动物的认知缺陷，并确定介导这些缺陷的突触信号传导缺陷。最后，我们将研究kalirin损失如何影响体内突触结构和功能。因为阿尔茨海默病（AD）的特征在于认知和树突棘缺陷，其与由卡林下调诱导的那些密切平行，并且因为卡林损失是人类阿尔茨海默病患者的共同特征，所以理解卡林在体内的作用具有极端的治疗相关性。总的来说，提出的目标将对理解树突棘功能障碍如何影响体内学习记忆产生巨大影响，这是神经科学领域的一个推测，但知之甚少。此外，由于卡林损失在阿尔茨海默氏症患者的前脑中是明显的，并且由于我们提出了初步证据表明卡林损失是细胞阿尔茨海默氏症模型的特征，因此卡林KO小鼠的表征可以与另外的研究结合，将卡林鉴定为治疗靶点，如已经针对卡林效应分子Pak和GluR 1所建议的。树突棘是大脑中大多数兴奋性突触的部位。通过了解树突棘内的信号分子如何影响棘密度/形态以及这些分子如何影响认知功能，如学习和记忆，将确定更好地理解棘畸变如何影响认知。此外，了解突触功能障碍对认知的影响对于更全面地了解阿尔茨海默病的病理学具有根本的重要性。

DESCRIPTION (provided by applicant): Dendritic spines are the sites of most excitatory synapses in the brain. Changes in spine density and morphology are of significance for the formation of learning and memory, and spine dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that likely directly contributes to cognitive dysfunctions. The Rho GEF kalirin has been shown to control dendritic spine morphogenesis via its activation of the small GTPase Rac. Rac in turn activates the p21-activated kinase, Pak, which in turn mediates actin cytoskeletal rearrangement and consequent changes in spine morphology. The recent development of the first kalirin KO mouse will be used to determine if the previously characterized kalirin- Rac and kalirin-GluR1 in vitro interactions are dysregulated in kalirin KO animals in vivo. Furthermore we will characterize the cognitive deficits of kalirin KO animals and determine the synaptic signaling deficits that mediate these deficits. Last, we will examine how kalirin loss affects synaptic structure and function in vivo. Because Alzheimer's disease (AD) is characterized by cognitive and dendritic spine deficits that closely parallel those induced by kalirin down-regulation, and because kalirin loss is a common feature of human Alzheimer's patients, understanding the role of kalirin in vivo is of extreme therapeutic relevance. Overall, the proposed aims will have enormous implications for understanding how dendritic spine dysfunctions affect learning a memory in vivo, an area of neuroscience is much is speculated, but little is known. In addition, because kalirin loss is evident in the forebrain of Alzheimer's patients, and because we present preliminary evidence indicating that kalirin loss is characteristic of a cellular Alzheimer's model, the characterization of the kalirin KO mouse may in conjunction with addition studies identify kalirin as a therapeutic target as has been suggested for the kalirin effector molecules Pak and GluR1. Lay Summary: Dendritic spines are sites of most excitatory synapses in the brain. By understanding how signaling molecules within dendritic spines affect spine density/morphology and how these molecules affect cognitive functions such as learning and memory, a better understanding how spine aberrations affect cognition will be determined. In addition, an understanding of the effects of synaptic dysfunction on cognition is of fundamental importance to more completely understanding the pathology of Alzheimer's disease.