Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission

Abstract

The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how the landscape of trans-synaptic bridges dynamically remodels to reflect functional states of the synapse. Here we developed novel optical tools to visualize in firing synapses the molecular behavior of a particular secreted trans-synaptic protein, LGI1, and its presynaptic receptor, ADAM23, and discovered that neuronal activity acutely rearranges the abundance of these proteins at the synaptic cleft. Surprisingly, LGI1 in synapses was not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitated the formation of trans-synaptic connections proportionally to the history of activity of the synapse, modulating excitatory transmission correlatively to synaptic firing rates. Thus, our findings reveal that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as critical point of activity-dependent control of synaptic function.

LGI1 autoantibodies enhance synaptic transmission by presynaptic Kv1 loss and increased action potential broadening

“…18 Furthermore, LGI1-overexpression shortened presynaptic action potentials in primary hippocampal cultures, leading to lower action potential-evoked calcium entry and hence glutamate release. 56 Therefore, LGI1 autoantibodies induce effects that are reminiscent of those observed in LGI1 knock-out mice and thus support the mechanistic model that LGI1 increases the presynaptic potassium channel density, shortens the presynaptic action potential duration, lowers the release probability, and thereby dampens neuronal activity.…”

Activity-driven trafficking of endogenous synaptic proteins through proximity labeling

“…As such, it should also enable distinguishing functionally, rather than biochemically 61,62 , whether a protein is located in a trafficking organelle. Increasing evidence shows that non-canonical synaptic vesicle proteins can translocate to the synaptic surface during neuronal activity, yet direct proof of such trafficking occurring for the endogenous proteins remains unproven 12–15 . As a proof of concept, we show that endogenous NPTX1 and ATG9A are translocated to the synaptic surface, providing important biological insight into the functioning of these proteins at the synapses.…”

“…NPTX1-pHluorin was designed to express pHluorin after the NPTX1 c-terminus using a linker previously shown to not affect the properties of LGI1, a different trans-synaptic organizer 12 . Using Gibson Assembly (NEBuilder® HiFi DNA Assembly Master Mix, New England Biolabs, E2621), we used CamKII-LGI1-pH (Addgene Plasmid #185537) to replace LGI1 by rat NPTX1 (a gift from Dr. Jonathan Elegheert, Uniprot #P47971).…”

Comparative Effects of Domain-Specific Human Monoclonal Antibodies Against LGI1 on Neuronal Excitability

“… 10 , 11 Recent imaging data of fluorescently labeled LGI1 argue against secretion but for cycling of LGI1 by exo- and endocytosis. 12 The homodimerization of LGI1 is mediated by mutual binding of the LRR domain of one LGI1 molecule to the EPTP domain of the second LGI1 and the EPTP propeller structure interacts directly with their receptors: ADAM22 and ADAM23. 13 Hence, LGI1 is proposed to serve as a transsynaptic linker molecule connecting presynaptic voltage-gated potassium channels of K v 1.1 type and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in a multiprotein complex.…”