Molecular Mechanisms of Age-related Synaptic Disorganization

描述（由申请人提供）：随着智慧的增长，年龄会给神经功能带来许多令人不快的变化：记忆力下降，反应能力和行动能力下降，大脑变得更容易生病。虽然这些现象有很好的文献记载，但对它们的分子基础却知之甚少。为了阐明随着年龄增长而发生的神经系统改变，我们将研究重点放在视觉系统的突触上，这些突触适合高分辨率分析，并且位于与年龄相关的显著功能退化的部位。在最近的一项研究中（塞缪尔等人）。J. Neurosci. 2011)，我们发现随着视网膜的老化，不同的神经元在其神经突结构上表现出不同的形态变化，并与其突触伙伴产生异常的连接。初步研究表明，这些变化伴随着特定丝氨酸/苏氨酸激酶LKB1的失调，并可能由这种失调引起。LKB1是细胞代谢的中心调节剂，磷酸化并激活能量传感器AMPK。我们发现年老的视网膜神经元显示AMPK的激活明显降低，同时神经元错误连接的水平也很高。此外，在幼龄动物中LKB1的缺失导致外视网膜重新布线的表型与在老年动物中观察到的相同。因此，保护或恢复LKB1-AMPK通路的干预措施可能会阻止与年龄相关的神经元连接变化。我现在提出了一系列研究，旨在研究LKB1能量稳态通路调节神经元衰老的分子机制，并确定新的突触衰老基因。具体来说，我将：(1)剖析LKB1的作用

DESCRIPTION (provided by applicant): 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 at the site of significant age-related functional deterioration. n 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 miswiring. 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 neuro 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.