Integrins and LTP consolidation

描述（由申请人提供）：一些证据表明，长期增强（LTP）是普通形式记忆的基础。像记忆一样，LTP也有一个巩固阶段，因此它在诱导后很容易在短时间内中断，但随后会逐渐变得更加稳定。一旦得到巩固，LTP可以在动物生命的很大一部分时间内持续存在。LTP的细胞解释面临的一个巨大挑战是确定与巩固时间过程一致的机制，与增强的传播具有逻辑关系，并且仍然能够产生异常长寿的变化。计划中的研究是对先前赠款的延续，将检验一个似乎满足这些限制的特定假设。该假说涉及整合素，这是一类跨膜蛋白，它将细胞外基质与细胞内细胞骨架连接起来，从而产生锚定细胞的粘附连接。申请人和其他人的工作在突触（大脑的主要粘附连接）中发现了几种不同的整合素，并进一步表明其中一定数量的整合素在LTP巩固中起着关键作用。拟议的研究将测试海马体中的以下序列：a) LTP的触发事件激活整合素，然后b)修饰突触谷氨酸受体，c)重组肌动蛋白细胞骨架。从非神经系统的角度来看，这些事件中的最后一个能够产生极其稳定的变化。四个具体目标将用于检验整合素/LTP稳定假说。目的一将确定刺激谷氨酸受体是否通过将整合素从静止状态转化为活跃状态和/或增加其表面表达来增加整合素信号传导。目的二将确定整合素对谷氨酸受体的上调是否包括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。目的三将测试是否肌动蛋白聚合在成人脊柱，一个影响最近发现的申请人伴随LTP，是由整合素发起的。目的四将确定低频刺激引起的近期LTP逆转是否由于腺苷介导的肌动蛋白聚合阻滞。这些实验的结果有望为LTP（因此可能是记忆）是如何得到巩固的特定假设提供强有力的检验。

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.