Hippocampal Synaptic Structure

描述（由申请人提供）：这是一个关于衰老过程中海马神经元钙（Ca2+）相关过程失调以及神经元功能/易感性改变的后果的长期项目的续期申请的重新提交。该项目最初源于发现Ca2+依赖性慢后超极化（sAHP），在海马锥体神经元的动作电位爆发之后，在老年动物中比在年轻的成年动物中更大。重要的是，较大的sahp与神经元兴奋性降低和学习记忆受损有关。相反，在学习任务的动物中发现了较小的sahp。从那时起，我们和其他人已经确定Ca2+动作电位，Ca2+瞬态和l型Ca2+电流也在衰老神经元中增加。这些结果导致了脑衰老的Ca2+失调假说，其中l通道活动的增加起着关键的启动作用，由此产生的较大的sAHP降低了神经元的兴奋性。此外，ryanodine受体（RyRs）中Ca2+诱导的Ca2+释放（CICR）的增强调节锥体神经元中衰老相关的Ca2+瞬态和sahp的大小也变得很明显。该项目的主要目标是从根本上推进我们对导致不健康大脑衰老的Ca2+失调的潜在分子机制的理解。基于我们新的有趣的结果，我们已经制定了一个新的与年龄相关的Ca2+失调的工作假设，表明下调亲免疫蛋白，特别是FK-506结合蛋白1b和/或1a (FKBP1b/1a)，导致RyR不稳定级联，更大的CICR和更大的sahp。其结果是神经元兴奋性和行为可塑性受损。这些研究将通过显微注射病毒载体在体内操纵FKBP- Ca2+调节通路中FKBP1b/1a和其他蛋白的海马表达/功能。将使用多学科方法评估同一动物的多种结果，包括广泛的行为测试，最先进的细胞内电生理学与伴随的Ca2+成像，免疫组织化学和基因微阵列分析。这些研究应充分阐明依赖于Ca2+失调的衰老变化，并应明确测试FKBPs在衰老过程中Ca2+失调和海马功能中的作用。慢性干预研究可能具有直接的翻译相关性，并直接导致针对衰老相关脑功能下降的新型预防和治疗方法。鉴于老龄化人口的急剧增加，确定和开发这样的治疗方法来维持老年人的认知功能变得越来越重要。

DESCRIPTION (provided by applicant): This is the resubmission of a renewal application for a longstanding project on dysregulation of calcium (Ca2+)-related processes in hippocampal neurons during aging and the consequences for altered neuronal function/vulnerability. The project initially derived from the finding that the Ca2+-dependent slow afterhyperpolarization (sAHP), that follows a burst of action potentials in hippocampal pyramidal neurons, is larger in aged than in young-adult animals. Importantly, larger sAHPs are correlated with reduced neuronal excitability and impaired learning and memory. Conversely, smaller sAHPs are found in animals that learn a task. Since then, we and others have determined that Ca2+ action potentials, Ca2+ transients and L-type Ca2+ currents also are increased in aged neurons. These results led to a Ca2+ dysregulation hypothesis of brain aging, in which increased activity of L-channels plays a key initiating role and the resulting larger sAHP reduces neuronal excitability. It also has become apparent that enhanced Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs) modulates the magnitude of aging-related Ca2+ transients and sAHPs in pyramidal neurons. The major objective of this project is to fundamentally advance our understanding of the underlying molecular mechanisms of Ca2+ dysregulation that lead to unhealthy brain aging. Based on our new intriguing results, we have formulated a novel working hypothesis of age-related Ca2+ dysregulation that suggests that downregulation of immunophilins, particularly FK-506 binding protein 1b and/or 1a (FKBP1b/1a), leads to a cascade of RyR destabilization, greater CICR and larger sAHPs. The resulting effect is impaired neuronal excitability and behavioral plasticity. These studies will manipulate hippocampal expression/function of FKBP1b/1a and other proteins in the FKBP- Ca2+ regulatory pathway in vivo using microinjection of viral vectors. Multiple outcomes will be assessed in the same animals using a multidisciplinary approach comprising extensive behavioral testing, state-of-the-art intracellular electrophysiology with concomitant Ca2+ imaging, immunohistochemistry, and gene microarray analysis. These studies should substantially elucidate aging changes that depend on Ca2+ dysregulation and should clearly test the role of FKBPs in Ca2+ dysregulation and hippocampal function during aging. Chronic intervention studies are proposed that could have direct translational relevance and lead directly to novel preventative and therapeutic treatments against aging-related decline of brain function. Given the dramatic increase in the aging population, it is becoming increasingly important to identify and develop such therapies to maintain cognitive function in the elderly.