LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding
Ji Won Um,
Tae-Yong Choi,
Hyeyeon Kang,
Yi Sul Cho,
Gayoung Choii,
Pavel Uvarov,
Dongseok Park,
Daun Jeong,
Sangmin Jeon,
Dongmin Lee,
Hyun Kim,
Seung-Hee Lee,
Yong-Chul Bae,
Se-Young Choi,
Matti S. Airaksinen,
Jaewon Ko
Affiliations
Ji Won Um
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea
Tae-Yong Choi
Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Korea
Hyeyeon Kang
Department of Physiology and BK21 PLUS Project to Medical Sciences, Yonsei University College of Medicine, Seoul 120-751, Korea
Yi Sul Cho
Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea
Gayoung Choii
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea
Pavel Uvarov
Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki 14, Finland
Dongseok Park
Department of Physiology and BK21 PLUS Project to Medical Sciences, Yonsei University College of Medicine, Seoul 120-751, Korea
Daun Jeong
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
Sangmin Jeon
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea
Dongmin Lee
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
Hyun Kim
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
Seung-Hee Lee
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
Yong-Chul Bae
Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea
Se-Young Choi
Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Korea
Matti S. Airaksinen
Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki 14, Finland
Jaewon Ko
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea
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.
