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

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.

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.

Metrics

  • 2,013
    views
  • 212
    downloads
  • 25
    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. 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
(2014)
Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/Neuregulin 1 signalling
eLife 3:e02196.
https://doi.org/10.7554/eLife.02196

Share this article

https://doi.org/10.7554/eLife.02196

Further reading

    1. Neuroscience
    Song Chang, Beilin Zheng ... Liping Yu
    Research Article

    Multisensory object discrimination is essential in everyday life, yet the neural mechanisms underlying this process remain unclear. In this study, we trained rats to perform a two-alternative forced-choice task using both auditory and visual cues. Our findings reveal that multisensory perceptual learning actively engages auditory cortex (AC) neurons in both visual and audiovisual processing. Importantly, many audiovisual neurons in the AC exhibited experience-dependent associations between their visual and auditory preferences, displaying a unique integration model. This model employed selective multisensory enhancement for the auditory-visual pairing guiding the contralateral choice, which correlated with improved multisensory discrimination. Furthermore, AC neurons effectively distinguished whether a preferred auditory stimulus was paired with its associated visual stimulus using this distinct integrative mechanism. Our results highlight the capability of sensory cortices to develop sophisticated integrative strategies, adapting to task demands to enhance multisensory discrimination abilities.

    1. Computational and Systems Biology
    2. Neuroscience
    Brian DePasquale, Carlos D Brody, Jonathan W Pillow
    Research Article Updated

    Accumulating evidence to make decisions is a core cognitive function. Previous studies have tended to estimate accumulation using either neural or behavioral data alone. Here, we develop a unified framework for modeling stimulus-driven behavior and multi-neuron activity simultaneously. We applied our method to choices and neural recordings from three rat brain regions—the posterior parietal cortex (PPC), the frontal orienting fields (FOF), and the anterior-dorsal striatum (ADS)—while subjects performed a pulse-based accumulation task. Each region was best described by a distinct accumulation model, which all differed from the model that best described the animal’s choices. FOF activity was consistent with an accumulator where early evidence was favored while the ADS reflected near perfect accumulation. Neural responses within an accumulation framework unveiled a distinct association between each brain region and choice. Choices were better predicted from all regions using a comprehensive, accumulation-based framework and different brain regions were found to differentially reflect choice-related accumulation signals: FOF and ADS both reflected choice but ADS showed more instances of decision vacillation. Previous studies relating neural data to behaviorally inferred accumulation dynamics have implicitly assumed that individual brain regions reflect the whole-animal level accumulator. Our results suggest that different brain regions represent accumulated evidence in dramatically different ways and that accumulation at the whole-animal level may be constructed from a variety of neural-level accumulators.