Molecular Mechanisms of Age-related Synaptic Disorganization

描述(申请人提供)：随着年龄的增长，神经功能会发生许多令人不快的变化：记忆力下降，反应能力和灵活性下降，大脑更容易受到疾病的影响。虽然这些现象都有很好的记载，但人们对它们的分子基础知之甚少。为了阐明随年龄增长而发生的神经变化，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位置。在最近的一项研究中(Samuel等人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轴突结构的形态变化，并与它们的突触伙伴发展异常的连接。初步研究表明，这些变化伴随着一种特定的丝氨酸/苏氨酸激酶LKB1的失调，而且可能是这种失调的结果。LKB1是细胞代谢的中央调节器，它能磷酸化并激活能量感受器AMPK。我们发现，陈旧的视网膜神经元表现出明显的AMPK活性降低，这与神经元高度连接错误的情况是一致的。此外，在幼年动物中LKB1的缺失导致外部视网膜重新布线，其表型与在老年动物中观察到的相同。因此，保留或恢复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性变化。我现在提出一系列研究，旨在研究LKB1能量稳态途径调节神经元衰老的分子机制，并识别新的突触衰老基因。具体来说，我将：(1)剖析LKB1的作用 AMPK通路在视网膜外部错误连接中的作用；(2)确定这些信号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，我将对错误连接的神经元亚群进行转录图谱分析，以确定与年龄相关的神经元衰退的其他分子相关性。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.