REGULATION OF DENDRITIC SPINES

描述（来自申请人摘要） 这一建议涉及分子控制的基本机制， 树突棘的稳定性树突棘是微特化的 突触后膜，是突触的主要部位， 接触许多哺乳动物前脑神经元参与记忆和 认知.初步研究表明，树突棘 在短暂暴露于谷氨酸激动剂NMDA后不稳定。 体内突触作为正常过程的一部分而不稳定和丢失 活动依赖的突触选择。此外，脊柱缺失可能 构成兴奋性毒性神经元细胞死亡的初始阶段，或 与衰老有关的突触减少。对那些 有助于脊柱的相对稳定和不稳定 因此可能有助于开发治疗方法， 干预认知能力下降的最早阶段 伴随正常衰老或退行性疾病。拟议的研究 将利用基于荧光的成像方法来研究特定的 关于谷氨酸诱导的棘突机制的假说 不稳定来自大鼠脑海马的培养神经元将被 用作模型系统。的时间和药理学特性 谷氨酸对棘的作用将被确定， 突触外因素对脊柱稳定性的影响。刺 假设具有收缩特性，因此 肌动蛋白、肌动蛋白结合蛋白和Rho家族的小GTP酶将 使用免疫细胞化学和肌动蛋白显微注射进行研究， 定向探针。目前的调查将使用一个细胞 生物学方法来确定潜在的分子机制 脊柱调节

DESCRIPTION (from applicant's abstract) This proposal addresses fundamental mechanisms in the molecular control of dendritic spine stability. Dendritic spines are micro-specializations of the postsynaptic membrane, and are the prevalent sites of synaptic contact in many mammalian forebrain neurons involved in memory and cognition. Preliminary studies show that dendritic spines are rapidly destabilized following brief exposures to the glutamate agonist NMDA. In vivo synapses are destabilized and lost as part of the normal process of activity-dependent synapse selection. In addition spine loss may constitute an initial stage in excitotoxic neuronal cell death or synaptic decreases related to aging. An understanding of factors that contribute to the relative stabilization and destabilization of spines may therefore facilitate development of therapeutic approaches to intervene a the very earliest stages of the cognitive decline accompanying normal aging or degenerative disease. The proposed studies will utilize fluorescence-based imaging methods to investigate specific hypotheses regarding the mechanism of glutamate-induced spine destabilization. Cultured neurons from rat brain hippocampus will be used as a model system. The temporal and pharmacological properties of glutamate's action on spines will be determined, and the contribution of extra-synaptic factors to spine stability will be explored. Spines are hypothesized to have contractile properties, therefore the roles of actin, actin-binding proteins, and the Rho family of small GTPases will be investigated using immunocytochemistry and microinjection of actin- directed probes. The present investigation will utilize a cell biological approach to determine the molecular mechanism underlying spine regulation.