1. Cell Biology
  2. Neuroscience

Distinct neurexin-cerebellin complexes control AMPA- and NMDA-receptor responses in a circuit-dependent manner

  1. Jinye Dai  Is a corresponding author
  2. Kif Liakath-Ali
  3. Samantha Rose Golf
  4. Thomas C Südhof  Is a corresponding author
  1. Howard Hughes Medical Institute, Stanford University, United States
  2. Stanford University, United States
https://doi.org/10.7554/eLife.78649
Share this article
Cite this article
  1. Jinye Dai
  2. Kif Liakath-Ali
  3. Samantha Rose Golf
  4. Thomas C Südhof
(2022)
Distinct neurexin-cerebellin complexes control AMPA- and NMDA-receptor responses in a circuit-dependent manner
eLife 11:e78649.
https://doi.org/10.7554/eLife.78649
  2. Download BibTeX
  3. Download .RIS

Abstract

At CA1àsubiculum synapses, alternatively spliced neurexin-1 (Nrxn1SS4+) and neurexin-3 (Nrxn3SS4+) enhance NMDA-receptors and suppress AMPA-receptors, respectively, without affecting synapse formation. Nrxn1SS4+ and Nrxn3SS4+ act by binding to secreted cerebellin-2 (Cbln2) that in turn activates postsynaptic GluD1 receptors. Whether neurexin-Cbln2-GluD1 signaling has additional functions besides regulating NMDA- and AMPA-receptors, and whether such signaling performs similar roles at other synapses, however, remains unknown. Here, we demonstrate using constitutive Cbln2 deletions in mice that at CA1àsubiculum synapses, Cbln2 performs no additional developmental roles besides regulating AMPA- and NMDA-receptors. Moreover, low-level expression of functionally redundant Cbln1 did not compensate for a possible synapse-formation function of Cbln2 at CA1àsubiculum synapses. In exploring the generality of these findings, we examined the prefrontal cortex where Cbln2 was recently implicated in spinogenesis, and the cerebellum where Cbln1 is known to regulate parallel-fiber synapses. In the prefrontal cortex, Nrxn1SS4+-Cbln2 signaling selectively controlled NMDA-receptors without affecting spine or synapse numbers, whereas Nrxn3SS4+-Cbln2 signaling had no apparent role. In the cerebellum, conversely, Nrxn3SS4+-Cbln1 signaling regulated AMPA-receptors, whereas now Nrxn1SS4+-Cbln1 signaling had no manifest effect. Thus, Nrxn1SS4+- and Nrxn3SS4+-Cbln1/2 signaling complexes differentially control NMDA- and AMPA-receptors in different synapses in diverse neural circuits without regulating synapse or spine formation.

Data availability

All numerical data and P values within this study have been included in the manuscript.

Article and author information

Author details

  1. Jinye Dai

    Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, United States
    For correspondence
    jinye.dai@mssm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8497-3154

  2. Kif Liakath-Ali

    Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9047-7424

  3. Samantha Rose Golf

    Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Thomas C Südhof

    Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, United States
    For correspondence
    tcs1@stanford.edu
    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

Funding

National Institute of Mental Health (MH052804)

  • Thomas C Südhof

European Molecular Biology Organization (ALTF 803-2017)

  • Kif Liakath-Ali

Larry L. Hillblom Foundation (2020-A-016-FEL)

  • Kif Liakath-Ali

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

Ethics

Animal experimentation: All mouse studies were performed according to protocols (#18846) approved by the Stanford University Administrative Panel on Laboratory Animal Care.

Copyright

© 2022, Dai et al.

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.

Metrics

  • 2,515
    views
  • 512
    downloads
  • 16
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jinye Dai
  2. Kif Liakath-Ali
  3. Samantha Rose Golf
  4. Thomas C Südhof
(2022)
Distinct neurexin-cerebellin complexes control AMPA- and NMDA-receptor responses in a circuit-dependent manner
eLife 11:e78649.
https://doi.org/10.7554/eLife.78649

Share this article

https://doi.org/10.7554/eLife.78649

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella

    Yajun Zhai, Peiyi Liu ... Gongzheng Hu
    Research Article

    Discovering new strategies to combat the multidrug-resistant bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed a weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this article, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL against mcr-1- and mcr-1+ Salmonella strains either in vitro or in vivo, when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD, or MCR using the natural compound AS could be further investigated as an attractive strategy for the treatment of Salmonella infection. Collectively, our work opens new avenues toward the potentiation of COL and reveals an alternative drug combination strategy to overcome COL-resistant bacterial infections.

    1. Cell Biology

    A ‘torn bag mechanism’ of small extracellular vesicle release via limiting membrane rupture of en bloc released amphisomes (amphiectosomes)

    Tamás Visnovitz, Dorina Lenzinger ... Edit I Buzas
    Short Report

    Recent studies showed an unexpected complexity of extracellular vesicle (EV) biogenesis pathways. We previously found evidence that human colorectal cancer cells in vivo release large multivesicular body-like structures en bloc. Here, we tested whether this large EV type is unique to colorectal cancer cells. We found that all cell types we studied (including different cell lines and cells in their original tissue environment) released multivesicular large EVs (MV-lEVs). We also demonstrated that upon spontaneous rupture of the limiting membrane of the MV-lEVs, their intraluminal vesicles (ILVs) escaped to the extracellular environment by a ‘torn bag mechanism’. We proved that the MV-lEVs were released by ectocytosis of amphisomes (hence, we termed them amphiectosomes). Both ILVs of amphiectosomes and small EVs separated from conditioned media were either exclusively CD63 or LC3B positive. According to our model, upon fusion of multivesicular bodies with autophagosomes, fragments of the autophagosomal inner membrane curl up to form LC3B positive ILVs of amphisomes, while CD63 positive small EVs are of multivesicular body origin. Our data suggest a novel common release mechanism for small EVs, distinct from the exocytosis of multivesicular bodies or amphisomes, as well as the small ectosome release pathway.