Molecular dissection of glia-neuron interactions

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PROJECT SUMMARY Our long-term aim is to understand glial roles in nervous system health, aging and disease in molecular detail. The human nervous system has about equal numbers of glia cells and neurons, and interactions between these two cell types is critical for neural functions. An important site of contact between glia and neurons is the neuron-ending, where neurons receive input from other neurons (interneuron dendritic spine) or the environment (sensory receptive-endings). Neuron-ending shape dictates appropriate neuron connectivity and functions, including sensory perception and learning and memory. While it is appreciated that glia modulate neuron-ending shapes and functions, molecular mechanisms underlying this remain poorly defined. Indeed, many fundamental principles of glia-neuron interactions remain unclear, such as whether all glia-neuron pairs interact using identical molecular mechanisms. It is however important to address this gap in our understanding of glial functions, because impaired glia-neuron interactions are implicated in many neurological diseases such as Alzheimer’s disease, Autism, epilepsy and may contribute to neural decline with age. We propose to dissect glia-neuron interactions in molecular detail in vivo, using C. elegans as a powerful and genetically amenable experimental platform. C. elegans glia resemble vertebrate glia, and our recent studies have validated this as a powerful setting to rapidly probe glia-neuron molecular interactions. We previously identified two novel molecular mechanisms by which glia interact with neurons to regulate their shape, functions and associated animal behaviors. All molecular components of these mechanisms that we have uncovered so far are broadly expressed, suggesting that aspects of glia-neuron interactions are evolutionarily conserved across species. Importantly, C. elegans glia are accessible for rapid and reproducible genetic and cellular manipulations in vivo. Effects of such manipulation can be investigated at multiple levels of inquiry, from molecular (genetic, genomic, protein biochemistry), cell-biology (cell shape, cell-cell contacts) and circuits (functional imaging, mapped connectome) to animal behavior and aging studies, and disease models (Alzheimer’s, Parkinson’s). Here, we propose to dissect molecular mechanisms of glia-neuron interactions throughout animal age in detail. For this, we will couple the experimental platform we established, and techniques described above, with the multiple genetic mutants we recently identified to (1) determine how multiple molecular pathways together enable interactions between a single glia-neuron pair; (2) investigate in mechanistic detail how a single glia can differentiate associated neurons to regulate them differently, and (3) dissect mechanisms by which different glia-neuron pairs interact to regulate neuron functions with age. Together, these studies will build a comprehensive molecular framework of how a glia cell modulates the functions of associated neurons throughout animal an animal’s lifespan.