Glial control of neuronal receptive ending morphology

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Our long-term aim is to understand the mechanism by which neuronal receptive-ending shape is altered by experience. In the nervous system, cell shape is malleable. Neuronal receptive endings, such as dendritic spines and sensory protrusions, are structurally remodelled by experience, and an emerging hypothesis in cellular neuroscience is that these shape changes accommodate and define changes in neuron output. Alterations in receptive-ending structures may, therefore, underlie nervous system plasticity, and may contribute to complex cognitive capacities including learning and memory. How receptive-ending structures acquire and change shape is not well understood; however, it has been assumed that a direct response of postsynaptic neurons to presynaptic activity accounts for most aspects of the phenomenon. Here we challenge this view, suggesting that glial cells associated with receptive endings play major roles in determining receptive-ending shape, and therefore function, together with presynaptic cues. Glia are the most abundant cell type in the human brain, and glia contribute extensively to nervous system disease. However, the roles played by glia in the nervous system remain largely mysterious. Several observations suggest that glia could influence the shapes of neuronal receptive-endings: they are in the right place at the right time, they can sense the postsynaptic milieu, their shapes correlate dynamically with neuronal receptive-ending cell shapes, and mutations in some glial proteins affect receptive ending shape. We previously demonstrated that the nematode C. elegans offers a unique arena in which to explore glial functions in the nervous system, allowing in vivo studies of glial function to be adresed in ways curently not posible in vertebrate settings or even in Drosophila. We propose to use the powerful methods of genetic analysis in C. elegans to uncover 1) the molecular mechanisms by which glia affect neuronal shape, and 2) how remodeling afects neurons function and animal behavior. In the longer term, we plan to explore conservation of the pathways we identify beyond C. elegans. Achieving a comprehensive understanding of the mechanisms that endow nervous systems with anatomic and behavioural plasticity is of paramount importance in understanding the brain. Such an understanding should, eventually, allow us to tackle human disorders, including learning disabilities and autism, which may result from alterations in synaptic function and plasticity. PUBLIC HEALTH RELEVANCE: Achieving a comprehensive understanding of the mechanisms that endow nervous systems with the ability to change in response to experience is of paramount importance in understanding learning, memory and other aspects of the brain. Such an understanding should ultimately allow us to tackle human disorders, including learning disabilities and autism, which may result from defects in such. Our studies describe a novel system, the nematode C. elegans, with the potential to unlock some of the mechanisms leading to experience-dependent changes in behavior.