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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057667-02
Application #
7227437
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Talley, Edmund M
Project Start
2006-05-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$328,433
Indirect Cost
Name
Brown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Dunaevsky, Anna (2012) Neuron-glial interactions in the developing cerebellum. Microsc Microanal 18:742-4
Lippman Bell, Jocelyn J; Lordkipanidze, Tamar; Cobb, Natalie et al. (2010) Bergmann glial ensheathment of dendritic spines regulates synapse number without affecting spine motility. Neuron Glia Biol 6:193-200
Lippman, Jocelyn J; Lordkipanidze, Tamar; Buell, Margaret E et al. (2008) Morphogenesis and regulation of Bergmann glial processes during Purkinje cell dendritic spine ensheathment and synaptogenesis. Glia 56:1463-77