Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity

Yuri Miyazaki, Takeshi Otsuka, Yoko Yamagata, Toshihiro Endo, Makoto Sanbo, Hiromi Sano, Kenta Kobayashi, Hiroki Inahashi, Hans-Christian Kornau, Dietmar Schmitz, Harold Prüss, Dies Meijer, Masumi Hirabayashi, Yuko Fukata, Masaki Fukata*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism, involve altered synaptic transmission and plasticity. Functional characterization of their associated genes is vital for understanding physio-pathological brain functions. LGI3 is a recently recognized ID-associated gene encoding a secretory protein related to an epilepsy-gene product, LGI1. Here, we find that LGI3 is uniquely secreted from oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons, forming nanoscale subclusters. Proteomic analysis using epitope-tagged Lgi3 knockin mice shows that LGI3 uses ADAM23 as a receptor and selectively co-assembles with Kv1 channels. A lack of Lgi3 in mice disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. Collectively, this study identifies an extracellular organizer of juxtaparanodal Kv1 channel clustering for finely tuned synaptic transmission. Given the defective secretion of the LGI3 missense variant, we propose a molecular pathway, the juxtaparanodal LGI3-ADAM23-Kv1 channel, for understanding neurodevelopmental disorders.

Original languageEnglish
Pages (from-to)1-29
JournalCell Reports
Publication statusPublished - 23 Jan 2024

Keywords / Materials (for Non-textual outputs)

  • LGI3
  • ADAM23
  • Kv1 channel
  • juxtaparanode
  • oligodendrocyte
  • short-term synaptic plasticity
  • intellectual disability
  • nanocluster
  • STED
  • neurodevelopmental disorders


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