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

突触的中心功能是将电信号形式的信息转化为化学信号，化学信号可以将该信息传递给其他细胞。这一基本过程允许神经回路的进化，以控制复杂的行为和认知功能。我们对突触传递的遗传基础的大部分了解来自于对特定生物体的研究，包括啮齿动物、线虫、果蝇和酵母。然而，我们对远亲动物之间突触的分子组成和功能如何进行广泛的比较，以及在动物多细胞出现后突触是如何进化的，我们知之甚少。这样的理解对加拿大人来说是重要的，也是有益的，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得出的结果提供关键视角，这些动物模型系统通常用于模拟突触信号异常的人类神经疾病。在过去的五年里，在我的第一笔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和重要的发现。在进一步的支持下，我们将继续并致力于三个相互关联的研究目标：1.粘着木霉(Trichoplax Adhaerens)中质子、神经肽和甘氨酸对神经递质受体信号的进化。Trichoplax是一种简单的动物，由于缺乏神经系统和突触，与我们的原始祖先相似。然而，Trichoplax细胞以神经元般的方式相互通信，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细胞信号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Deg/NAC通道，以及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通道是突触前终末神经递质释放、突触后信号传递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，并描绘出其独特功能的结构决定因素。3.Cav通道突触蛋白复合体的进化。CAV通道在突触中的功能在很大程度上依赖于它们与突触支架蛋白的不同相互作用。在这里，我们试图通过基因组分析和生物信息学结合湿实验室研究来了解这些蛋白质复合体的多样性和进化。

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.