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The long-term goal of this study is to understand the molecular and cellular mechanisms that regulate the development of cerebellar neuronal circuits. Dendritic spines, sites of synaptic input on many projection neurons such as the cerebellar purkinje cell are highly dynamic structures and their motility is developmentally regulated. The mechanisms that regulate spine dynamics over development are not known. Here, we will use multiphoton live imaging of neuronal structures in organotypic slices and in vivo, in conjunction with electron microscopy to study the mechanisms of synaptic maintenance. Our central hypothesis is that ensheathment by glial processes critically regulates dendritic spine motility and synaptic stability. In the first aim we will characterize the development of Bergmann glia processes using static and dynamics imaging approaches. In the second aim we will test how spine dynamics is regulated by glial ensheathment by measuring spine motility in genetic models with reduced glial ensheathment. In the third aim we will determine the role of EphA receptors and the ephrin ligands in glia-spine cross talk and regulation of spine dynamics. Finally, we will determine how synaptic maintenance is related to spine motility and is regulated by glial processes. Abnormal development of neuronal connections can be the cause of neurodevelopmental disorders in humans. Moreover, recently it has been demonstrated that abnormal glial- neuron interactions during development might cause mental disorders in the adult. Therefore, understanding the cellular and molecular mechanisms of glial-neuron interactions during synapse formation and maintenance has important health significance.
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