Neurotransmission requires a precise number and arrangement of receptors, ion channels, and adhesion molecules at synapses. Alterations in the localization or levels of these proteins at the postsynaptic membrane regulates synapse function, thereby strengthening or weakening synaptic connections in the brain. In all eukaryotic cells, removal of membrane proteins of diverse types occurs by clathrin-mediated endocytosis. Although previous studies have helped define the endocytic machinery in nonneuronal cells and the presynaptic nerve terminal, the location and regulation of clathrin-mediated endocytosis within postsynaptic compartments and its functional role in synaptic signaling remain unknown. To address these important questions, my laboratory has initiated a program of biochemical and cell biological studies to analyze the endocytic machinery of dendritic spines - the primary postsynaptic compartment in the mammalian brain. We have recently found that dendritic spines contain a zone of clathrin assembly and endocytosis adjacent to, but spatially segregated from, the postsynaptic density. This endocytic zone forms and persists over long periods of time independent of synaptic activity, and serves to concentrate cargo destined for internalization. Taking advantage of these preliminary data and our ability to monitor and manipulate clathrin assembly and cargo uptake in neurons, we propose to define the underlying molecular and cellular mechanisms that form, maintain and regulate the endocytic zone of spines, and determine the functional consequences for spine maturation and synaptic transmission. This work will provide insight into fundamental mechanisms that underlie synapse formation and synaptic plasticity. Moreover, because clathrin-mediated endocytosis regulates neuronal responsiveness to a wide range of pathologic insults and therapeutic agents relevant to numerous neurologic and psychiatric diseases, these studies hold promise for the development of novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047574-02
Application #
7037602
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Stewart, Randall R
Project Start
2005-04-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$347,756
Indirect Cost
Name
Duke University
Department
Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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