The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

Abstract

Glutamatergic synapses rely on AMPA receptors (AMPARs) for fast synaptic transmission and plasticity. AMPAR auxiliary proteins regulate receptor trafficking, and modulate receptor mobility and its biophysical properties. The AMPAR auxiliary protein Shisa7 (CKAMP59) has been shown to interact with AMPARs in artificial expression systems, but it is unknown whether Shisa7 has a functional role in glutamatergic synapses. We show that Shisa7 physically interacts with synaptic AMPARs in mouse hippocampus. Shisa7 gene deletion resulted in faster AMPAR currents in CA1 synapses, without affecting its synaptic expression. Shisa7 KO mice showed reduced initiation and maintenance of long-term potentiation of glutamatergic synapses. In line with this, Shisa7 KO mice showed a specific deficit in contextual fear memory, both short-term and long-term after conditioning, whereas auditory fear memory and anxiety-related behavior were normal. Thus, Shisa7 is a bona-fide AMPAR modulatory protein affecting channel kinetics of AMPARs, necessary for synaptic hippocampal plasticity, and memory recall.

Article and author information

Author details

  1. Leanne J M Schmitz

    Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  2. Remco V Klaassen

    Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  3. Marta Ruiperez-Alonso

    Department of Integrative Neurophysiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  4. Azra Elia Zamri

    Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  5. Jasper Stroeder

    Department of Integrative Neurophysiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  6. Priyanka Rao-Ruiz

    Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  7. Johannes C Lodder

    Department of Integrative Neurophysiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  8. Rolinka J van der Loo

    Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  9. Huib D Mansvelder

    Department of Integrative Neurophysiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1365-5340
  10. August B Smit

    Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    August B Smit, Participates in a holding that owns shares of Sylics BV.
  11. Sabine Spijker

    Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
    For correspondence
    s.spijker@vu.nl
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6814-2019

Funding

HEALTH-2009-2.1.2.1 EU-FP7 SynSys (SynSys)

  • Marta Ruiperez-Alonso
  • Jasper Stroeder
  • Huib D Mansvelder
  • August B Smit
  • Sabine Spijker

Erasmus Mundus (159302-1-2009-1-NL-ERA MUNDUS-EMJD)

  • Azra Elia Zamri

NWO-ALW #822.02.020 (#822.02.020)

  • Remco V Klaassen

NBSIK PharmaPhenomics FES0908 (FES0908)

  • Leanne J M Schmitz
  • Rolinka J van der Loo
  • August B Smit

NBSIK Mouse Phenomics Consortium BSIK03053 (BSIK03053)

  • Priyanka Rao-Ruiz
  • Rolinka J van der Loo
  • August B Smit

MEST-CT-2005-020919 Neuromics (20919)

  • Priyanka Rao-Ruiz

MEST-ITN-2008-238686 CerebNet (238686)

  • Jasper Stroeder

NWO-ALW Vici 865.13.002 (865.13.002)

  • Huib D Mansvelder

ERC BrainSignals 281443 (281443)

  • Huib D Mansvelder

NWO-ALW Vici 016.150.673 / 865.14.002 (016.150.673 / 865.14.002)

  • Leanne J M Schmitz
  • Sabine Spijker

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 experiments were performed in accordance to Dutch law and licensing agreements using a protocol approved by the Animal Ethics Committee of the VU University Amsterdam.

Reviewing Editor

  1. Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Korea (South), Republic of

Publication history

  1. Received: January 18, 2017
  2. Accepted: December 2, 2017
  3. Accepted Manuscript published: December 4, 2017 (version 1)
  4. Version of Record published: December 20, 2017 (version 2)
  5. Version of Record updated: January 11, 2018 (version 3)
  6. Version of Record updated: May 4, 2018 (version 4)

Copyright

© 2017, Schmitz 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.

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  1. Leanne J M Schmitz
  2. Remco V Klaassen
  3. Marta Ruiperez-Alonso
  4. Azra Elia Zamri
  5. Jasper Stroeder
  6. Priyanka Rao-Ruiz
  7. Johannes C Lodder
  8. Rolinka J van der Loo
  9. Huib D Mansvelder
  10. August B Smit
  11. Sabine Spijker
(2017)
The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory
eLife 6:e24192.
https://doi.org/10.7554/eLife.24192
  1. Further reading

Further reading

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