Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission

Cell Rep. 2024 May 28;43(5):114186. doi: 10.1016/j.celrep.2024.114186. Epub 2024 May 2.

Abstract

The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how trans-synaptic bridges change to reflect the functional states of the synapse. Here, we develop optical tools to visualize in firing synapses the molecular behavior of two trans-synaptic proteins, LGI1 and ADAM23, and find that neuronal activity acutely rearranges their abundance at the synaptic cleft. Surprisingly, synaptic LGI1 is primarily not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitates the formation of trans-synaptic connections proportionally to the history of activity of the synapse, adjusting excitatory transmission to synaptic firing rates. Accordingly, we find that patient-derived autoantibodies against LGI1 reduce its surface fraction and cause increased glutamate release. Our findings suggest that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as a critical control point for synaptic function.

Keywords: ADAM23; CP: Cell biology; CP: Neuroscience; LGI1; anti-LGI1 limbic encephalitis; epilepsy; neurotransmission; optical sensors; synapse; trans-synaptic connections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism
  • Animals
  • Autoantibodies / immunology
  • Glutamic Acid / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Synapses* / metabolism
  • Synaptic Transmission* / physiology

Substances

  • ADAM Proteins
  • Autoantibodies
  • Glutamic Acid
  • Intracellular Signaling Peptides and Proteins
  • LGI1 protein, human
  • Lgi1 protein, rat