Latrophilin GPCR signaling mediates synapse formation

  1. Richard Sando  Is a corresponding author
  2. Thomas C Südhof
  1. Stanford University School of Medicine, United States


Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In mouse CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.

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All raw numerical data within the study has been submitted together with the manuscript.

Article and author information

Author details

  1. Richard Sando

    Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1797-2346
  2. Thomas C Südhof

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3361-9275


National Institute of Mental Health (K99-MH117235)

  • Richard Sando

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.


Animal experimentation: All procedures strictly conformed to National Institutes of Health Guidelines for the Care and Use of Laboratory Mice and were approved by the Stanford University Administrative Panel on Laboratory Animal Care (APLAC) and institutional animal care and use committee (IACUC). The animal protocol #20787 was approved by Stanford University APLAC and IACUC. All surgeries were performed under Avertin anesthesia and buprenorphine analgesia, and every effort was made to minimize suffering, pain and distress.

Reviewing Editor

  1. Graeme W Davis, University of California, San Francisco, United States

Version history

  1. Received: December 13, 2020
  2. Accepted: February 26, 2021
  3. Accepted Manuscript published: March 1, 2021 (version 1)
  4. Version of Record published: March 12, 2021 (version 2)


© 2021, Sando & Südhof

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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  1. Richard Sando
  2. Thomas C Südhof
Latrophilin GPCR signaling mediates synapse formation
eLife 10:e65717.

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