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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)808-822
Number of pages15
JournalCell Reports
Volume14
Issue number4
DOIs
Publication statusPublished - 2016 Feb 2

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Keywords

  • Alternative splicing
  • Dentate gyrus
  • Excitatory synapse development
  • Glypican
  • LRRTM3
  • LRRTM4
  • Neurexin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Um, J. W., Choi, T. Y., Kang, H., Cho, Y. S., Choii, G., Uvarov, P., Park, D., Jeong, D., Jeon, S., Lee, D., Kim, H., Lee, S. H., Bae, Y. C., Choi, S. Y., Airaksinen, M. S., & Ko, J. (2016). LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding. Cell Reports, 14(4), 808-822. https://doi.org/10.1016/j.celrep.2015.12.081