Synapses represent polarized, specialized intercellular junctions and constitute the major points of communication between neurons in the brain. At a synapse, the presynaptic neuron secretes neurotransmitters that are then recognized by the postsynaptic cell. Synaptic junctions are formed by interactions between pre- and postsynaptic membranes but little is known about the molecular basis for these interactions. Alpha- and beta-neurexins constitute a polymorphic family of neuron-specific, cell surface proteins that are expressed from three genes. Indirect evidence suggests that these proteins function as cell adhesion and signaling molecules in synaptic junctions. The evidence includes the observation of a large number of neurexin isoforms generated by alternative splicing (>1000 isoforms), the finding that an alternatively-spliced subset of beta-neurexins binds to a novel neuronal cell adhesion molecule called neuroligin, which is also localized to synapses, and the fact that intracellular complexes of synaptic proteins assemble on neurexins via PDZ-domain interactions. Furthermore, knockout mice revealed that the deletion of alpha-neurexins causes a selective deficit in symmetric synapses. The overall hypothesis that will be tested in the current grant application is that neurexins function as synaptic cell adhesion and recognition molecules and contribute to the formation and maintenance of synaptic junctions.
Four specific aims are proposed to test this hypothesis. The first specific aim will examine the precise localization of neurexins. The second analyzes their functions genetically in knockout mice. The third specific aim will characterize the functions of neurexins as cell adhesion molecules and signaling receptors, and the fourth specific aim will study the intracellular interactions of neurexins with PDZ-domain proteins that link the neurexins to synaptic vesicle traffic and the actin cytoskeleton. Together, these experiments will provide insight into the function of this highly conserved neuron-specific family of proteins and extend our understanding of how synapses are formed and maintained.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH052804-10
Application #
6743207
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (03))
Program Officer
Asanuma, Chiiko
Project Start
1994-09-30
Project End
2005-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
10
Fiscal Year
2004
Total Cost
$273,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Seigneur, Erica; Südhof, Thomas C (2018) Genetic Ablation of All Cerebellins Reveals Synapse Organizer Functions in Multiple Regions Throughout the Brain. J Neurosci 38:4774-4790
Südhof, Thomas C (2018) Towards an Understanding of Synapse Formation. Neuron 100:276-293
Seigneur, Erica; Polepalli, Jai S; Südhof, Thomas C (2018) Cbln2 and Cbln4 are expressed in distinct medial habenula-interpeduncular projections and contribute to different behavioral outputs. Proc Natl Acad Sci U S A 115:E10235-E10244
Li, Jingxian; Shalev-Benami, Moran; Sando, Richard et al. (2018) Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse. Cell 173:735-748.e15
Zhang, Bo; Gokce, Ozgun; Hale, W Dylan et al. (2018) Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses. J Exp Med 215:1543-1553
Chanda, Soham; Hale, W Dylan; Zhang, Bo et al. (2017) Unique versus Redundant Functions of Neuroligin Genes in Shaping Excitatory and Inhibitory Synapse Properties. J Neurosci 37:6816-6836
Anderson, Garret R; Maxeiner, Stephan; Sando, Richard et al. (2017) Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly. J Cell Biol 216:3831-3846
Chew, Kylie S; Fernandez, Diego C; Hattar, Samer et al. (2017) Anatomical and Behavioral Investigation of C1ql3 in the Mouse Suprachiasmatic Nucleus. J Biol Rhythms 32:222-236
Polepalli, Jai S; Wu, Hemmings; Goswami, Debanjan et al. (2017) Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network. Nat Neurosci 20:219-229
Südhof, Thomas C (2017) Molecular Neuroscience in the 21st Century: A Personal Perspective. Neuron 96:536-541

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