Molecular and cellular mechanisms that underlie synaptic maturation

在所有的神经系统中，从无脊椎动物到人类，新形成的突触连接尚未发挥最佳功能。所有的突触都必须经历一个突触成熟的过程，从结构简单和功能不完善的连接过渡到结构复杂的连接，能够强大的突触传递和可塑性。这一过程至关重要，因为突触成熟的失败与健康和疾病有着显著的关系，潜在的神经发育障碍如自闭症和癫痫，以及智力障碍如精神分裂症。最近的研究甚至表明，成熟过程也可能在阿尔茨海默氏症等神经退行性疾病中被劫持。尽管如此重要，突触成熟的分子机制仍然知之甚少。结构事件，包括招募突触后蛋白到新生的突触前末梢，必须先于功能成熟，但即使是我们的基因和途径，使这些事件的理解仍然不完整。具体来说，参与成熟的突触前受体仍然研究不足，我们对成熟信号如何在突触后处理以促进发育的理解仍然存在重大差距。这项提案的长期目标是确定确保正常突触成熟的分子，并确定它们发挥作用的机制。为了理解这些基本事件，我们将使用遗传学，高分辨率成像和生物化学方法的组合来研究突触成熟的机制。我们的初步工作已经确定了三个跨膜蛋白，可能在结构突触成熟的功能。这些基因的突变与早发性阿尔茨海默病、神经元分化失败和肌萎缩侧索硬化症有关，强调了它们在正常功能的神经系统中的重要性。我们将首先描述这些分子中的每一个如何有助于突触的生长和成熟。接下来，我们将确定这些基因在哪里表达，以及它们是否在突触前或突触后介导突触成熟。最后，我们将开始确定这些基因发挥功能的机制，并与已建立的调节突触成熟和发育的信号通路交叉。我们希望这项工作将首先确定在突触前和突触后发挥作用以确保突触成熟的新基因，其次是它们实现这一目标的机制。随着对这些基因的正常功能的更深入了解，我们可以更好地了解它们如何在存在时避免阿尔茨海默病等疾病，以及这些基因的突变如何有助于神经退行性疾病的进展。通过这样做，我们将为成熟背后的细胞事件建立一个基本的基础，并开始告知受损的突触成熟如何成为神经发育障碍、智力残疾和神经退行性疾病的基础。

In all nervous systems, from invertebrates to humans, newly formed synaptic connections are not yet optimally functional. All synapses must undergo a process of synaptic maturation to transition from structurally simple and functionally unrefined connections to structurally complex connections capable of robust synaptic transmission and plasticity. This process is critically important, as failures in synaptic maturation have a marked bearing in health and disease, underlying neurodevelopmental disorders like autism and epilepsy and intellectual disabilities like schizophrenia. Recent work has even suggested that the maturation process may also be hijacked in neurodegenerative diseases like Alzheimer’s. Despite this importance, the molecular mechanisms that underlie synaptic maturation remain poorly understood. Structural events including the recruitment of postsynaptic proteins to nascent presynaptic terminals must preface functional maturation, but even our understanding of the genes and pathways that enable these events remains incomplete. Specifically, the presynaptic receptors involved in maturation remain woefully understudied and there are still critical gaps in our understanding of how established maturation signals are processed postsynaptically to promote development. The long-term goal of this proposal is to identify the molecules that ensure normal synaptic maturation and determine the mechanisms by which they function. To understand these fundamental events, we will use a combination of genetics, high-resolution imaging, and biochemistry approaches to investigate the mechanisms that underlie synaptic maturation. Our preliminary work has identified three transmembrane proteins that likely function in structural synaptic maturation. Mutations in these genes have been associated with early-onset Alzheimer’s disease, failures in neuronal differentiation, and amyotrophic lateral sclerosis, underscoring their importance in a normally functioning nervous system. We will first characterize how each of these molecules contributes to synaptic growth and maturation. Following, we will determine where these genes are expressed and whether they function presynaptically or postsynaptically to mediate synaptic maturation. Finally, we will begin to determine the mechanism by which these genes function and intersect with established signaling pathways that regulate synaptic maturation and development. We expect that this work will first identify new genes that function pre- and postsynaptically to ensure synaptic maturation and second, the mechanisms by which they achieve this goal. With a deeper understanding of the normal function of these genes, we can better understand how they work to stave off disorders like Alzheimer’s disease when present and how mutations in those genes can contribute to the progression of neurodegenerative diseases. In so doing, we will establish a fundamental foundation for the cellular events underlying maturation and begin to inform how impaired synaptic maturation can underlie neurodevelopmental disorders, intellectual disabilities, and neurodegenerative diseases.