Studying mechanisms for the evolution of synaptic and electrical signaling in the nervous system

研究神经系统突触和电信号的进化机制

• 批准号: RGPIN-2021-03557
• 负责人: Senatore, Adriano
• 金额: $ 3.64万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742555
• 关键词: Studying; mechanisms; evolution; synaptic; electrical

The central function of synapses is to translate information in the form of electrical signals into chemical signals that can pass that information along to other cells. This fundamental process permitted the evolution of neural circuits for controlling complex behaviors and cognitive function. Much of our understanding about the genetic underpinnings of synaptic transmission comes from studies done in select organisms, including rodents, nematode worms, fruit flies and yeast. However, we know little about how the molecular composition and function of synapses compares broadly, between distantly related animals, and how the synapse evolved after the emergence of animal multicellularity. Such an understanding is important and beneficial to Canadians as it can illuminate the core genetic features of synaptic transmission, and provide crucial perspectives for interpreting and integrating findings made using different animal models systems, often used to model human neurological disorders where aberrant synaptic signaling is apparent. Over the past five years, with the support of my first NSERC Discovery grant, my team and I have pursued my long term research objective to better understand the mechanisms and evolution of synaptic transmission, and have made some exciting and important discoveries. With further support, we will continue and engage in three interrelated research objectives: 1. Evolution of neurotransmitter receptor signaling by protons, neuropeptides and glycine in Trichoplax adhaerens. Trichoplax is a simple animal that resembles our primordial ancestors by lacking a nervous system and synapses. Nevertheless, Trichoplax cells communicate with each other in a neuron-like manner to coordinate various directed motile behaviors, for example, towards food or away from light. We seek to understand the molecular underpinnings of cell signaling and motile behavior in Trichoplax, via secreted neuropeptides and protons that target synaptic ion channel receptors called Deg/NaC channels, and glycine that targets synaptic ion channels called ionotropic glutamate receptors. 2. Molecular evolution of voltage-gated calcium channels (i.e. CaV channels). CaV channels are required for neurotransmitter release at the pre-synaptic terminal, and post-synaptic signaling and muscle contraction. Through comparative structural analysis and electrophysiology, we seek to understand how the core distinguishing features of CaV channels came to be, and to delineate structural determinants for their unique functions. 3. Evolution of CaV channel synaptic protein complexes. The function of CaV channels at synapses depends greatly on their differential interactions with synaptic scaffolding proteins.  Here, we seek to understand the diversity and evolution of these protein complexes by combining genomic analysis and bioinformatics, with wet-lab research.

突触的核心功能是将电信号形式的信息转化为化学信号，然后将信息沿着传递给其他细胞。这一基本过程使得控制复杂行为和认知功能的神经回路得以进化。我们对突触传递的遗传基础的理解大部分来自于对特定生物体的研究，包括啮齿动物、蠕虫、果蝇和酵母。然而，我们对突触的分子组成和功能在远亲动物之间的广泛比较知之甚少，以及在动物多细胞出现后突触是如何进化的。这种理解对加拿大人来说是重要和有益的，因为它可以阐明突触传递的核心遗传特征，并为解释和整合使用不同动物模型系统所做的研究结果提供重要的视角，这些动物模型系统通常用于模拟异常突触信号传导明显的人类神经系统疾病。 在过去的五年里，在我的第一个NSERC发现基金的支持下，我和我的团队一直在追求我的长期研究目标，以更好地了解突触传递的机制和进化，并取得了一些令人兴奋的重要发现。在进一步的支持下，我们将继续从事三个相互关联的研究目标：1。粘毛藻中质子、神经肽和甘氨酸介导的神经递质受体信号的进化。Trichoplax是一种简单的动物，类似于我们的原始祖先，缺乏神经系统和突触。然而，Trichoplax细胞以神经元样的方式相互通信，以协调各种定向运动行为，例如，朝向食物或远离光线。我们试图了解Trichoplax中细胞信号传导和运动行为的分子基础，通过分泌的神经肽和质子靶向突触离子通道受体（称为Deg/NaC通道）和甘氨酸靶向突触离子通道（称为离子型谷氨酸受体）。2.电压门控钙通道（即CaV通道）的分子进化。CaV通道是突触前末端神经递质释放、突触后信号传导和肌肉收缩所必需的。通过比较结构分析和电生理学，我们试图了解CaV通道的核心区别特征是如何形成的，并描述其独特功能的结构决定因素。3. CaV通道突触蛋白复合物的进化。CaV通道在突触中的功能很大程度上取决于它们与突触支架蛋白的差异相互作用。在这里，我们试图通过结合基因组分析和生物信息学，以及湿实验室研究来了解这些蛋白质复合物的多样性和进化。