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达到最佳功能。所有突触都必须经历一个突触成熟的过程，才能从结构简单、功能不完善的连接过渡到结构复杂、具有强大突触传递和可塑性的连接。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，是自闭症、癫痫等神经发育障碍和精神分裂症等智力障碍的潜在原因。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，突触成熟背后的分子机制仍然知之甚少。包括突触后蛋白向新生突触前末端募集在内的结构事件必须先于功能成熟，但即使我们对这些事件的基因和途径的理解仍然不完整。具体来说，参与成熟的突触前受体仍然没有得到充分的研究，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。这项建议的长期目标是确定确保正常突触成熟的分子，并确定它们的功能机制。为了理解这些基本事件，我们将结合遗传学、高分辨率成像和生物化学方法来研究突触成熟的机制。我们的初步工作已经确定了三种跨膜蛋白可能在结构突触成熟中起作用。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如何促进突触的生长和成熟。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起作用，以介导突触成熟。最后，我们将开始确定这些基因的功能机制，并与调节突触成熟和发育的既定信号通路相交。我们期望这项工作将首先确定突触前和突触后功能的新基因，以确保突触成熟，其次，它们实现这一目标的机制。随着对这些基因正常功能的深入了解，我们可以更好地理解它们是如何避免阿尔茨海默病等疾病的，以及这些基因的突变是如何导致神经退行性疾病的进展的。这样，我们将为成熟背后的细胞事件建立一个基本的基础，并开始告知突触成熟受损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.