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.
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