Molecular Mechanisms of Age-related Synaptic Disorganization

描述（由申请人提供）：沿着智慧，年龄给神经功能带来了许多令人不快的变化：记忆力下降，反射和行动能力下降，大脑变得更容易生病。虽然这些现象有很好的文献记载，但对其分子基础知之甚少。为了阐明随着年龄的增长而发生的神经学变化，我们将研究重点放在视觉系统的突触上，这些突触可以进行高分辨率分析，并且处于与年龄相关的显著功能退化的部位。在最近的研究中（Samuel等人，J. Neurosci. 2011），我们发现随着视网膜老化，不同的神经元对其神经突结构表现出不同的形态学变化，并与其突触伙伴形成异常连接。初步研究表明，这些变化伴随着，并可能导致，一个特定的丝氨酸/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显着减少激活AMPK符合高水平的神经元布线错误。此外，在年轻动物中LKB 1的缺失导致外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神经元连接的年龄相关变化。我现在提出一系列研究，旨在研究LKB 1能量稳态途径调节神经元衰老的分子机制，并确定新的突触衰老基因。具体而言，我将：（1）剖析LKB 1的作用 AMPK通路在外视网膜错误布线;（2）确定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央投射神经节细胞的突触老化。与此同时，我将进行转录分析的神经亚群，错接，以确定额外的分子相关的年龄相关的神经元衰退。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。

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.