title: Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking.
abstract: Neurexins are essential presynaptic cell adhesion molecules that are linked to schizophrenia and autism and are subject to extensive alternative splicing. Here, we used a genetic approach to test the physiological significance of neurexin alternative splicing. We generated knockin mice in which alternatively spliced sequence #4 (SS4) of neuexin-3 is constitutively included but can be selectively excised by cre-recombination. SS4 of neurexin-3 was chosen because it is highly regulated and controls neurexin binding to neuroligins, LRRTMs, and other ligands. Unexpectedly, constitutive inclusion of SS4 in presynaptic neurexin-3 decreased postsynaptic AMPA, but not NMDA receptor levels, and enhanced postsynaptic AMPA receptor endocytosis. Moreover, constitutive inclusion of SS4 in presynaptic neurexin-3 abrogated postsynaptic AMPA receptor recruitment during NMDA receptor-dependent LTP. These phenotypes were fully rescued by constitutive excision of SS4 in neurexin-3. Thus, alternative splicing of presynaptic neurexin-3 controls postsynaptic AMPA receptor trafficking, revealing an unanticipated alternative splicing mechanism for trans-synaptic regulation of synaptic strength and long-term plasticity.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, CA 94305-5453, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Aoto
authors.forename: David C
authors.initials: DC
authors.lastname: Martinelli
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tabuchi
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D004705:Endocytosis; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism; D017774:Long-Term Potentiation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses
chemical_list: D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C583456:neurexin 3, mouse