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 andsynaptic 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 dynamcis is regulated by glial ensehathment by measuring spine motility in genetic models with reduced glial ensehthment. 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 mainetnance 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 synapseformation 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 #
5R01NS057667-04
Application #
7574435
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Talley, Edmund M
Project Start
2006-05-01
Project End
2010-06-30
Budget Start
2009-03-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$236,005
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