Integrins and LTP consolidation

描述(申请人提供)：几行证据表明，长时程增强(LTP)是常见形式记忆的底物。与记忆一样，LTP也有一个巩固阶段，在诱导后的短时间内很容易被破坏，但随后会逐渐变得更加稳定。一旦得到巩固，LTP可以在动物寿命的很大一部分时间内持续存在。对于LTP的细胞账户来说，一个巨大的挑战是确定与巩固的时间进程相一致的机制，与增强的传输具有逻辑关系，并且仍然能够产生超乎寻常的长寿变化。这项计划中的研究代表了先前拨款的扩展，将测试似乎满足这些限制的特定假设。这一假说涉及整合素，这是一类将细胞外基质与细胞内细胞骨架连接起来的跨膜蛋白，从而产生锚定细胞的黏附连接。申请者和其他人的工作确定了突触(大脑的主要黏附连接)中的几种不同的整合素，并进一步表明，其中一定数量的整合素在LTP的巩固中起着关键作用。拟议中的研究将测试海马区的以下序列：a)LTP的触发事件激活整合素，然后整合素b)修饰突触谷氨酸受体，c)重组肌动蛋白细胞骨架。据非神经系统所知，这些事件中的最后一种能够产生极其稳定的变化。四个特定的目标将被用来检验整合素/LTP稳定性假说。目的确定谷氨酸受体的刺激是否通过将整合素从静止状态转变为活性状态和/或增加其表面表达来增加整合素信号。目的二将确定整合素a)上调谷氨酸受体是否包括AMPA受体表面表达的增加以及b)是否依赖于肌动蛋白网络的变化。目的三将测试成人脊柱中的肌动蛋白聚合是否由整合素启动，这是申请人最近发现的一种伴随LTP的效应。目的四将确定最近通过低频刺激诱导的LTP的逆转是否是由于腺苷介导的肌动蛋白聚合的阻断。这些实验的结果有望提供一个关于LTP是如何巩固的特定假设的强有力的测试，因此可能是记忆。

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.