The long-term goal of these studies is to understand the molecular mechanism of synapse formation and target recognition in the central nervous system.
The aims of the research proposed in this application are: (1) to dissect the structural basis for the synaptogenic activity of neuroligin, a post-synaptic adhesion molecule that can trigger the assembly of pre-synaptic elements in contacting axons, (2) to identify receptors for neuroligin in the pre-synaptic cell, and (3) to analyze the role of neuroligin in vivo.
Aim 1 and Aim 2 will be studied with functional cell-based assays in vitro that permit direct manipulation of the pre- and post-synaptic machinery. The neurexin family of proteins will be studied as candidate neuroligin receptors, but at the same time we will perform an unbiased biochemical purification of all molecules that might associate with neuroligin during synapse formation. To analyze neuroligin function in vivo, hammer-head ribozymes will be generated that specifically degrade neuroligin mRNAs. These ribozymes will be expressed in the cerebellum of mice, either by gene transfer into selected cells with a viral vector or in a transgenic animal. Synapse formation is a crucial process in the generation of neuronal circuits in the brain. Aberrant synapse formation and synaptic dysfunction lead to severe nervous system disorders such as epilepsy, schizophrenia, and mental retardation. Neuroligins themselves have been implicated in mental retardation in humans. Besides nervous system disorders, understanding the mechanism of synapse formation will also be most important for controlling or stimulating the regeneration of synaptic circuits after injury, as for example the connectivity in the spinal cord after injuries that lead to paralysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045014-04
Application #
6999701
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Mamounas, Laura
Project Start
2003-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$303,350
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Koehnke, Jesko; Jin, Xiangshu; Budreck, Elaine C et al. (2008) Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2. Proc Natl Acad Sci U S A 105:1873-8
Koehnke, Jesko; Jin, Xiangshu; Trbovic, Nikola et al. (2008) Crystal structures of beta-neurexin 1 and beta-neurexin 2 ectodomains and dynamics of splice insertion sequence 4. Structure 16:410-21
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Futai, Kensuke; Kim, Myung Jong; Hashikawa, Tsutomu et al. (2007) Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin. Nat Neurosci 10:186-95
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Chih, Ben; Gollan, Leora; Scheiffele, Peter (2006) Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex. Neuron 51:171-8
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