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A Genetic study of Neuronal Signaling, Glutamate Accumulation,

and Stroke-Like Neuro-degeneration in C. elegans

 Our brain is buzzing with neuronal activity. Nerve cells relentlessly fire information at one another, releasing powerful stimulating molecules in the process, such as the neurotransmitter Glutamate. How do we keep order in this mayhem? How do we clear the synapse of Glutamate, and prevent it from spilling over between neuronal circuits? Glutamate is also a dangerous neurotransmitter, because its accumulation in the synapse is toxic to the surrounding neurons. Indeed, insufficient Glutamate clearance during stroke/brain ischemia causes neurodegeneration in a process called excitotoxicity. What are the pathological events that happen in excitotoxicity? Can we find ways to stop or slow-down the degenerative process once it started?

These are some of the questions that we study in our lab. To help us tackle these complicated topics, we use the microscopic, free-living nematode C. elegans. Although these worms look very different from humans, they provide an excellent animal model system, because cellular and molecular events are highly conserved in evolution and are very similar in nematodes and humans. C. elegans research offers a simplified core version of these conserved signaling cascades, and a set of very powerful research tools. Since these nematodes are transparent, we can use optogenetics to study neuronal activity in intact animals while we modify their ability to clear Glutamate from their synapses. We can use genetic analysis and a battery of readily available mutant strains to follow the process of excitotoxic neurodegeneration, and determine critical steps. Furthermore, we can examine the balance between these neurodegenerative processes and pro-survival signaling cascades that provide neuroprotection. The use of C. elegans therefore allows us to illuminate basic principles in neuronal neurophysiology, neurodegeneration, and neuroprotection, principles that could provide guidance in the understanding of similar processes in higher animals.    

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