Molecular Mechanisms of Age-related Synaptic Disorganization

项目总结 除了智慧，年龄还会给神经功能带来许多令人不快的变化：记忆力减退、反射和 流动性变差，大脑变得更容易受到疾病的影响。虽然这些现象很好 有文献记载，人们对它们的分子碱基知之甚少。为了阐明所发生的神经变化 随着年龄的增长，我们的研究重点放在视觉系统的突触上，这些突触对高度敏感的 分辨率分析是与年龄相关的功能显著恶化的部位.在最近的一项研究中 (Samuel et al.J.神经学2011)，我们发现随着视网膜的老化，不同的神经元表现出不同的 神经突起结构的形态变化及其与突触的异常联系 合伙人。初步研究表明，这些变化伴随着，而且可能是由 一种特定的丝氨酸/苏氨酸激酶LKB1的失调。LKB1是细胞新陈代谢的中枢调节器 并磷酸化并激活能量传感器AMPK。我们发现陈旧的视网膜神经元显示出明显的 AMPK活性降低与神经元高度扭曲相一致。此外，LKB1在 幼年动物导致外部视网膜重新布线，与老年动物观察到的表型相同。 因此，保留或恢复LKB1-AMPK通路的干预措施可能会阻止年龄相关的变化 神经元连接。我现在提议进行一系列研究，旨在研究 LKB1能量稳态通路调控神经元衰老，识别新的突触衰老基因。 具体地说，我将：(1)剖析LKB1-AMPK通路在视网膜外部连接错误中的作用；(2)确定 这些信令网络调节这一过程的机制；以及(3)将这些分析扩展到 中央投射神经节细胞的突触老化。同时，我将执行转录特征分析 错误连接的神经元亚群，以确定与年龄相关的神经元的其他分子相关性 拒绝。这些研究将确定能量失调在突触老化中的作用，并可能确定 影响认知维持和年龄相关疾病易感性的途径。

PROJECT SUMMARY Along with wisdom, age brings many unpleasant alterations in neural function: memory declines, reflexes and mobility deteriorate, and the brain becomes more susceptible to disease. Though these phenomena are well documented, little is known about their molecular bases. To elucidate the neurological alterations that occur with age, we have focused our studies on synapses of the visual system, which are amenable to high- resolution analysis and are a the site of significant age-related functional deterioration. In a recent study (Samuel et al. J. Neurosci. 2011), we found that as the retina ages, different neurons exhibit distinct morphologic changes to their neurite architecture and develop aberrant connections with their synaptic partners. Preliminary studies suggest that these changes are accompanied by, and may result from, dysregulation of a specific serine/threonine kinase, LKB1. LKB1 is a central modulator of cellular metabolism and phosphorylates and activates the energy sensor AMPK. We find that old retina neurons show markedly reduced activation of AMPK coincident with high levels of neuronal miswring. Moreover, deletion of LKB1 in young animal leads to outer retina rewiring phenotypically identical to that observed in aged animals. Therefore, interventions that preserve or restore the LKB1-AMPK pathway may prevent age-related changes in neuron connectivity. I now propose a set of studies designed to examine the molecular mechanisms by which the LKB1 energy homeostasis pathway modulates neuronal aging and identity new synaptic aging genes. Specifically, I will: (1) dissect the role of the LKB1-AMPK pathway in outer retina miswiring; (2) determine the mechanisms by which these signaling networks modulate this process; and (3) expand these analyses to synaptic aging of centrally projecting ganglion cells. In parallel, I will perform transcriptional profiling of neuron subsets that miswire in order to identify additional molecular correlates of age-related neuronal decline. These studies will define the role of energy misregulation in synaptic aging and may identify pathways that affect both cognitive maintenance and age-related disease susceptibility.