Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission
Ulku Cuhadar, Lorenzo Calzado-Reyes, Carlos Pascual-Caro, Aman S. Aberra, Andreas Ritzau‐Jost, Abhi Aggarwal, Keiji Ibata, Kaspar Podgorski, Michisuke Yuzaki, Christian Geis, Stefan Hallerman, Michael B. Hoppa, Jaime de Juan‐Sanz
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.