Molecular Mechanisms of Age-related Synaptic Disorganization

项目摘要 沿着智慧的增长，年龄也给神经功能带来了许多令人不快的变化：记忆力下降，反应能力下降， 活动能力下降，大脑变得更容易受到疾病的影响。虽然这些现象是好的， 虽然有文献记载，但对它们的分子基础知之甚少。为了阐明发生的神经学改变 随着年龄的增长，我们把研究的重点放在视觉系统的突触上，这些突触可以承受高- 分辨率分析，是一个显着的年龄相关的功能恶化的网站。在最近的一项研究中 （Samuel等人，J. Neurosci. 2011年），我们发现，随着视网膜年龄的增长，不同的神经元表现出不同的 它们的神经突结构发生形态学变化，并与它们的突触形成异常连接。 伙伴初步研究表明，这些变化是伴随着，并可能导致， 特异性丝氨酸/苏氨酸激酶LKB 1的失调。LKB 1是细胞代谢的中心调节剂 磷酸化并激活能量传感器AMPK。我们发现，老年视网膜神经元表现出明显的 AMPK的活化减少与高水平的神经元错扭一致。此外，LKB 1的缺失在 年轻的动物导致外部视网膜重新布线，表型上与在老年动物中观察到的相同。 因此，保护或恢复LKB 1-AMPK通路的干预措施可能会防止年龄相关的变化， 神经元连接我现在提出一系列研究，旨在检查分子机制， LKB 1能量稳态途径调节神经元老化并鉴定新的突触老化基因。 具体来说，我将：（1）剖析LKB 1-AMPK通路在外视网膜错误布线中的作用;（2）确定LKB 1-AMPK通路的作用。 这些信号网络调节这一过程的机制;（3）将这些分析扩展到 中枢投射神经节细胞的突触老化。与此同时，我会对 错误连接的神经元子集，以识别与年龄相关的神经元的其他分子相关物 下降这些研究将确定能量失调在突触老化中的作用， 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.