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

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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.