REGULATION OF DENDRITIC SPINES

树突棘的调节

• 批准号: 2758625
• 负责人: Shelley L Halpain
• 金额: $ 30.02万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-03 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2758625
• 关键词: NMDA receptors; actin binding protein; actins; calcium flux; dendrites; electron microscopy; glutamates; guanine nucleotide binding protein; hippocampus; immunocytochemistry; laboratory rat; microinjections; neuropharmacology; neuroregulation; neurotoxins; photochemistry; synapses; tissue /cell culture

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.

描述（来自申请人的摘要） 该提案解决了分子控制的基本机制 树突棘的稳定性。树突棘是微观特化 突触后膜，是突触的常见位点 许多与记忆和记忆有关的哺乳动物前脑神经元的接触 认识。初步研究表明树突棘迅速形成 短暂接触谷氨酸激动剂 NMDA 后不稳定。 作为正常过程的一部分，体内突触会不稳定并丢失 活动依赖性突触选择。此外，脊柱损失可能 构成兴奋毒性神经细胞死亡的初始阶段或 与衰老相关的突触减少。对影响因素的理解 有助于脊柱的相对稳定和不稳定 因此可能会促进治疗方法的发展 在认知能力下降的最早阶段进行干预 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 关于谷氨酸诱导脊柱机制的假设 不稳定。从大鼠大脑海马体中培养的神经元将 用作模型系统。时间和药理学特性 谷氨酸对脊柱的作用将被确定，并且贡献 将探讨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小 GTP 酶的 Rho 家族将 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。目前的研究将利用细胞 生物学方法来确定潜在的分子机制 脊柱调节。