1. Neuroscience
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Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/Neuregulin 1 signalling

  1. Pietro Fazzari
  2. An Snellinx
  3. Victor Sabonov
  4. Tariq Ahmed
  5. Lutgarde Serneels
  6. Annette Gartner
  7. S. Ali M Shariati
  8. Detlef Balschun
  9. Bart De Strooper  Is a corresponding author
  1. VIB Center for the Biology of Disease, KU Leuven, Belgium
  2. KU Leuven, Belgium
Research Article
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Cite this article as: eLife 2014;3:e02196 doi: 10.7554/eLife.02196

Abstract

Neuregulin 1 (NRG1) and the γ-secretase subunit APH1B have been previously implicated as genetic risk factors for schizophrenia and schizophrenia relevant deficits have been observed in rodent models with loss of function mutations in either gene. Here we show that the Aph1b-γ-secretase is selectively involved in Nrg1 intracellular signalling. We found that Aph1b-deficient mice display a decrease in excitatory synaptic markers. Electrophysiological recordings show that Aph1b is required for excitatory synaptic transmission and plasticity. Furthermore, gain and loss of function and genetic rescue experiments indicate that Nrg1 intracellular signalling promotes dendritic spine formation downstream of Aph1b-γ-secretase in vitro and in vivo. In conclusion, our study sheds light on the physiological role of Aph1b-γ-secretase in brain and provides a new mechanistic perspective on the relevance of NRG1 processing in schizophrenia.

Article and author information

Author details

  1. Pietro Fazzari

    VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  2. An Snellinx

    VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  3. Victor Sabonov

    KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  4. Tariq Ahmed

    KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  5. Lutgarde Serneels

    VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  6. Annette Gartner

    VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  7. S. Ali M Shariati

    VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  8. Detlef Balschun

    KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  9. Bart De Strooper

    VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium
    For correspondence
    bart.destrooper@cme.vib-kuleuven.be
    Competing interests
    Bart De Strooper, Reviewing editor, eLife, and it might be perceived as a potential conflict of interest that I (BDS) am consultant for Janssen Pharmaceutica, Remynd NV and Envivo Pharmaceutics.

Ethics

Animal experimentation: All the experiments involving animals in this study were approved and performed in strict accordance with the recommendations of the Ethical Committee of Katholic Univesitet Leuven (Approval Nr. p047/2012). Every effort was taken to minimize suffering of mice according to the guidelines Ethical Committee.

Reviewing Editor

  1. Eunjoon Kim, Korea Advanced Institute of Science and Technology, South Korea

Publication history

  1. Received: January 2, 2014
  2. Accepted: May 29, 2014
  3. Accepted Manuscript published: June 2, 2014 (version 1)
  4. Accepted Manuscript updated: June 5, 2014 (version 2)
  5. Version of Record published: July 1, 2014 (version 3)

Copyright

© 2014, Fazzari 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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