Integrins and LTP consolidation

描述（由申请人提供）：几条证据表明，长时程增强（LTP）是常见形式的记忆的基质。像记忆一样，LTP也有一个巩固阶段，因此在诱导后的短时间内很容易受到干扰，但随后会逐渐变得更加稳定。一旦巩固，LTP可以持续动物生命的很大一部分。对LTP的细胞解释来说，一个巨大的挑战是确定与巩固的时间进程相一致的机制，与增强的传输有逻辑关系，并且仍然能够产生非凡的长寿变化。计划中的研究是对先前赠款的扩展，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，一类连接细胞外基质和细胞内细胞骨架的跨膜蛋白，从而产生锚细胞的粘附连接。申请人和其他人的工作确定了突触（大脑的初级粘附连接）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巩固中起关键作用。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，然后整合素B）修饰突触谷氨酸受体和c）重组肌动蛋白细胞骨架。最后一个事件是从非神经系统中得知的，能够产生极其稳定的变化。将使用四个特定目标来检验整合素/LTP稳定化假设。目的研究谷氨酸受体的刺激是否通过整合素从静止状态转化为活性状态和/或增加其表面表达来增加整合素信号传导。目的二是确定整合素上调谷氨酸受体a）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（申请人最近发现的伴随LTP的效应）是否由整联蛋白引发。目的四将确定是否逆转最近诱导的LTP低频刺激是由于腺苷介导的肌动蛋白聚合的阻滞。这些实验的结果有望为一个关于LTP以及可能的记忆如何变得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.