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.

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.

Metrics

  • 4,245
    views
  • 648
    downloads
  • 38
    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. 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

Share this article

https://doi.org/10.7554/eLife.24192

Further reading

    1. Neuroscience
    Samyogita Hardikar, Bronte Mckeown ... Jonathan Smallwood
    Research Article

    Complex macro-scale patterns of brain activity that emerge during periods of wakeful rest provide insight into the organisation of neural function, how these differentiate individuals based on their traits, and the neural basis of different types of self-generated thoughts. Although brain activity during wakeful rest is valuable for understanding important features of human cognition, its unconstrained nature makes it difficult to disentangle neural features related to personality traits from those related to the thoughts occurring at rest. Our study builds on recent perspectives from work on ongoing conscious thought that highlight the interactions between three brain networks – ventral and dorsal attention networks, as well as the default mode network. We combined measures of personality with state-of-the-art indices of ongoing thoughts at rest and brain imaging analysis and explored whether this ‘tri-partite’ view can provide a framework within which to understand the contribution of states and traits to observed patterns of neural activity at rest. To capture macro-scale relationships between different brain systems, we calculated cortical gradients to describe brain organisation in a low-dimensional space. Our analysis established that for more introverted individuals, regions of the ventral attention network were functionally more aligned to regions of the somatomotor system and the default mode network. At the same time, a pattern of detailed self-generated thought was associated with a decoupling of regions of dorsal attention from regions in the default mode network. Our study, therefore, establishes that interactions between attention systems and the default mode network are important influences on ongoing thought at rest and highlights the value of integrating contemporary perspectives on conscious experience when understanding patterns of brain activity at rest.