Integrins and LTP consolidation

整合素和 LTP 整合

• 批准号: 7244423
• 负责人: GARY S LYNCH
• 金额: $ 24.47万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244423
• 关键词: AMPA Receptors; Accounting; Actins; Acute; Adenosine; Adherens Junction; Adhesions; Adult; Agonist; Animals; Antibodies; Brain; Cells; Chemosensitization; Chromosome Pairing; Class; Cytoskeletal Proteins; Cytoskeleton; Dendritic Spines; Event; Extracellular Matrix; Frequencies; Glutamate Receptor; Grant; Hippocampus (Brain); Integral Membrane Protein; Integrins; Laboratories; Learning; Long-Term Potentiation; Longevity; Measures; Mediating; Membrane; Memory; Modification; N-Methyl-D-Aspartate Receptors; Numbers; Operative Surgical Procedures; PTK2 gene; PTK2B gene; Phase; Phosphorylation; Play; Process; Protein Tyrosine Kinase; Proteins; Role; Signal Transduction; Slice; Spectrin; Surface; Synapses; System; Techniques; Testing; Time; Transcriptional Activation; Up-Regulation; Vertebral column; Work; inhibitor/antagonist; neutralizing antibody; polymerization; prevent; receptor; receptor expression; relating to nervous system; research study; response; transmission process

DESCRIPTION (provided by applicant): Several lines of evidence indicate that long-term potentiation (LTP) is the substrate for commonplace forms of memory. Like memory, LTP has a consolidation phase such that it is easily disrupted for a short period after its induction but then becomes progressively more stable. Once consolidated, LTP can persist for a significant portion of the animal's lifespan. A great challenge for cellular accounts of LTP is to identify mechanisms that align with the time course of consolidation, have a logical relationship to enhanced transmission, and are still capable of producing changes of extraordinary longevity. The planned studies, which represent an extension of a previous grant, will test a specific hypothesis that appears to satisfy these constraints. The hypothesis involves integrins, a class of transmembrane proteins that connect the extracellular matrix to the intracellular cytoskeleton, and thereby generate the adhesion junctions that anchor cells. Work by the applicants and others identified several different integrins in synapses (the brain's primary adhesion junctions) and further showed that a certain number of these play a critical role in LTP consolidation. The proposed studies will test for the following sequence in hippocampus: a) the triggering events for LTP activate integrins, which then b) modify synaptic glutamate receptors and c) reorganize the actin cytoskeleton. The last of these events is known from non-neural systems to be capable of producing extremely stable changes. Four specific aims will be used to test the integrin/LTP stabilization hypothesis. Aim One will determine if stimulation of glutamate receptors increases integrin signaling by converting integrins from a quiescent to an active state and/or increasing their surface expression. Aim Two will determine if up-regulation of glutamate receptors by integrins a) includes increased AMPA receptor surface expression and b) is dependent upon changes in the actin network. Aim Three will test if actin polymerization in adult spines, an effect recently found by the applicants to accompany LTP, is initiated by integrins. Aim Four will determine if reversal of recently induced LTP by low frequency stimulation is due to an adenosine-mediated block of actin polymerization. The results of these experiments are expected to provide a strong test of a specific hypothesis regarding how LTP, and therefore possibly memory, becomes consolidated.

描述（由申请人提供）：几条证据表明，长期增强（LTP）是常见的记忆形式的底物。像内存一样，LTP具有一个合并阶段，因此在诱导后很容易将其在短时间内被干扰，但随后变得更加稳定。一旦合并，LTP可以持续到该动物寿命的很大一部分。对LTP的蜂窝帐户的一个巨大挑战是确定与合并时间过程保持一致的机制，与增强传输具有逻辑关系，并且仍然能够产生非凡的寿命变化。计划的研究代表了先前赠款的扩展，将检验一个似乎满足这些约束的特定假设。该假设涉及整联蛋白，整合素是一类将细胞外基质连接到细胞内细胞骨架的跨膜蛋白，从而产生锚定细胞的粘附连接。申请人和其他人的工作确定了突触中的几种不同整合蛋白（大脑的主要粘附连接），并进一步表明，其中一定数量在LTP合并中起着关键作用。拟议的研究将测试海马中的以下序列：a）LTP激活整联蛋白的触发事件，然后b）修改突触谷氨酸受体，c）重新组织肌动蛋白细胞骨架。这些事件中的最后一个是从非神经系统中知道的，能够产生极其稳定的变化。将使用四个具体目标来检验整联蛋白/LTP稳定假设。 AIM ONE将通过将整联蛋白从静止状态转换为活性状态和/或增加其表面表达来确定谷氨酸受体的刺激是否会增加整联蛋白的信号传导。目标两个将确定整合素对谷氨酸受体的上调是否包括增加AMPA受体表面表达，而B）取决于肌动蛋白网络中的变化。 AIM三将测试成年棘的肌动蛋白聚合是否是由整联蛋白启动的申请人最近发现的伴随LTP的效果。 AIM四将确定由于腺苷介导的肌动蛋白聚合块的逆转是否通过低频刺激逆转了LTP。这些实验的结果预计将对有关LTP（因此可能记忆）如何合并的特定假设提供了强有力的检验。