Grant: Operating Grant

The current model for brain development posits that initial guidance of axons and formation of connections is largely predetermined and controlled by molecular cues, whereas the plasticity leading to precise refinement of these connections is activity-dependent and can be influenced by sensory experience. We have studied this developmental interplay between molecular signalling and sensory experience using the retinotectal system of Xenopus laevis tadpoles. This model system has the advantages of being amenable to repeated imaging of living cells, electrophysiological recording, and single-cell genetic manipulations all in the intact, living animal. In addition to the neurons from the eye that project to synapse onto neurons in the brain, there is a third, often unappreciated player in this process: radial glial cells. The radial glia have long been known to be a source of the molecular guidance cues that help target retinal axons in the tectum. However, we made the surprising discovery that radial glial cells are also extraordinarily structurally dynamic cells, even more motile than the neurons with which they interact. During retinotectal map formation, they continually extend and retract long filopodial processes in all directions, greatly increasing their probability of interacting with ingrowing axons. Even more interestingly, we found the rate of their motility was modulated by sensory input. This means that rather than serving as passive molecular guideposts for ingrowing axons, the behaviour and presumably function of radial glia is also activity-dependent. The experiments in this proposal will elucidate the signalling pathways by which sensory experience regulates the motility of radial glia and the consequences of glial cell dynamics on neural circuit refinement and function. This work will provide new insights into how all the cells in the brain respond to early sensory experience to help build a highly efficient neural circuit.