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bioRxiv · 10.1101/2023.10.02.560463

Alternative Splicing of Latrophilin-3 Controls Synapse Formation

Wang, S.·Sudhof, T. C.·Sun, W.·Quake, S. R.·Roth, B. L.·DeLeon, C.
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Abstract

How synapses are assembled and specified in brain is incompletely understood. Latrophilin- 3, a postsynaptic adhesion-GPCR, mediates Schaffer-collateral synapse formation in the hippocampus but the mechanisms involved remained unclear. Here we show that Latrophilin-3 organizes synapses by a convergent dual-pathway mechanism by which Latrophilin-3 simultaneously activates GS/cAMP-signaling and recruits phase-separated postsynaptic protein scaffolds. We found that cell type-specific alternative splicing of Latrophilin-3 controls its G protein coupling mode, resulting in Latrophilin-3 variants that predominantly signal via Gs and cAMP or via G12/13. A CRISPR-mediated genetic switch of Latrophilin-3 alternative splicing from a GS- to a G12/13-coupled mode impaired synaptic connectivity similar to the overall deletion of Latrophilin-3, suggesting that GS/cAMP- signaling by Latrophilin-3 splice variants mediates synapse formation. Moreover, GS- but not G12/13-coupled splice variants of Latrophilin-3 recruit phase-transitioned postsynaptic protein scaffolds that are clustered by binding of presynaptic Latrophilin-3 ligands. Strikingly, neuronal activity promotes alternative splicing of the synaptogenic variant of Latrophilin-3, thereby enhancing synaptic connectivity. Together, these data suggest that activity- dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways, GS/cAMP signaling and the phase separation of postsynaptic protein scaffolds.

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Wang, S., Sudhof, T. C., Sun, W., Quake, S. R., Roth, B. L., DeLeon, C.. 2023-10-03. Alternative Splicing of Latrophilin-3 Controls Synapse Formation. https://doi.org/10.1101/2023.10.02.560463

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