DESCRIPTION (provided by applicant): The long-term goal of this proposal 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 dynamic imaging approaches. In the second aim, we will test how spine dynamics are regulated by glial ensehathment 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-neuronal interactions during development might cause mental disorders in the adult. Therefore, understanding the cellular and molecular mechanisms of glial-neuronal interactions during synapse formation and maintenance has important health significance.
|Effective start/end date||5/1/06 → 2/28/11|
- National Institutes of Health: $328,433.00
- National Institutes of Health: $335,275.00
- National Institutes of Health: $103,400.00
- National Institutes of Health: $339,713.00
- National Institutes of Health: $236,005.00