title: LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding.
abstract: The four members of the LRRTM family (LRRTM1-4) are postsynaptic adhesion molecules essential for excitatory synapse development. They have also been implicated in neuropsychiatric diseases. Here, we focus on LRRTM3, showing that two distinct LRRTM3 variants generated by alternative splicing regulate LRRTM3 interaction with PSD-95, but not its excitatory synapse-promoting activity. Overexpression of either LRRTM3 variant increased excitatory synapse density in dentate gyrus (DG) granule neurons, whereas LRRTM3 knockdown decreased it. LRRTM3 also controlled activity-regulated AMPA receptor surface expression in an alternative splicing-dependent manner. Furthermore, Lrrtm3-knockout mice displayed specific alterations in excitatory synapse density, excitatory synaptic transmission and excitability in DG granule neurons but not in CA1 pyramidal neurons. Lastly, LRRTM3 required only specific splice variants of presynaptic neurexins for their synaptogenic activity. Collectively, our data highlight alternative splicing and differential presynaptic ligand utilization in the regulation of LRRTMs, revealing key regulatory mechanisms for excitatory synapse development.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; Department of Physiology and BK21 PLUS Project to Medical Sciences, Yonsei University College of Medicine, Seoul 120-751, Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Um
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Choi
authors.affiliation: Department of Physiology and BK21 PLUS Project to Medical Sciences, Yonsei University College of Medicine, Seoul 120-751, Korea.
authors.forename: Hyeyeon
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea.
authors.forename: Yi Sul
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Gayoung
authors.initials: G
authors.lastname: Choii
authors.affiliation: Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki 14, Finland.
authors.forename: Pavel
authors.initials: P
authors.lastname: Uvarov
authors.affiliation: Department of Physiology and BK21 PLUS Project to Medical Sciences, Yonsei University College of Medicine, Seoul 120-751, Korea.
authors.forename: Dongseok
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
authors.forename: Daun
authors.initials: D
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Jeon
authors.affiliation: Department of Anatomy and Neuroscience, Korea 21 Biomedical Science, College of Medicine, Korea University, 126-1, 5-ka, Anam-dong, Seongbuk-gu, Seoul 136-705, Korea.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Neuroscience, Korea 21 Biomedical Science, College of Medicine, Korea University, 126-1, 5-ka, Anam-dong, Seongbuk-gu, Seoul 136-705, Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Bae
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Korea.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki 14, Finland.
authors.forename: Matti S
authors.initials: MS
authors.lastname: Airaksinen
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea. Electronic address: jaewonko@yonsei.ac.kr.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis; D021381:Protein Transport; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C000611753:LRRTM3 protein, mouse; C584075:LRRTM4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA
keywords: LRRTM3; LRRTM4; alternative splicing; dentate gyrus; excitatory synapse development; glypican; neurexin