REGULATION OF DENDRITIC SPINES

描述(摘自申请人的摘要) 这项建议解决了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，是突触的常见部位 许多哺乳动物前脑神经元中的接触与记忆和 认知力。初步研究表明，树突棘迅速地 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，体内突触的不稳定和丢失 依赖活动的突触选择。此外，脊椎丢失可能 构成兴奋性神经细胞死亡的初始阶段或 与衰老有关的突触减少。对以下因素的理解 有助于脊柱的相对稳定和不稳定 因此可以促进治疗方法的发展 干预认知衰退的最早阶段 伴随着正常的衰老或退行性疾病。建议进行的研究 将利用基于荧光的成像方法来研究特定的 谷氨酸诱导脊髓损伤机制的假说 不稳定。大鼠海马区培养的神经元将被 用作模型系统。丹参的时间和药理特性 谷氨酸对脊椎的作用将被确定，其贡献 将探索突触外因素对脊柱稳定性的影响。脊椎 被假设为具有收缩特性，因此 肌动蛋白、肌动蛋白结合蛋白和Rho家族的小GTP酶将 用免疫细胞化学和微量注射肌动蛋白- 定向探测器。目前调查将利用一间牢房 用生物学方法确定潜在的分子机制 脊椎调节。

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.