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

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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.

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Pietro Fazzari

VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium

Competing interests
No competing interests declared.
An Snellinx

VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium

Competing interests
No competing interests declared.
Victor Sabonov

KU Leuven, Leuven, Belgium

Competing interests
No competing interests declared.
Tariq Ahmed

KU Leuven, Leuven, Belgium

Competing interests
No competing interests declared.
Lutgarde Serneels

VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium

Competing interests
No competing interests declared.
Annette Gartner

VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium

Competing interests
No competing interests declared.
S. Ali M Shariati

VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium

Competing interests
No competing interests declared.
Detlef Balschun

KU Leuven, Leuven, Belgium

Competing interests
No competing interests declared.
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

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.