Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling
Pietro Fazzari,
An Snellinx,
Victor Sabanov,
Tariq Ahmed,
Lutgarde Serneels,
Annette Gartner,
S Ali M Shariati,
Detlef Balschun,
Bart De Strooper
Affiliations
Pietro Fazzari
VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium; Centre for Human Genetics, KU Leuven, Leuven, Belgium; Leuven Institute for Neuordegenerative Disorders (LIND), KU Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium
An Snellinx
VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium; Centre for Human Genetics, KU Leuven, Leuven, Belgium; Leuven Institute for Neuordegenerative Disorders (LIND), KU Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium
Victor Sabanov
Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium
Tariq Ahmed
Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium
Lutgarde Serneels
VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium; Centre for Human Genetics, KU Leuven, Leuven, Belgium; Leuven Institute for Neuordegenerative Disorders (LIND), KU Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium
Annette Gartner
VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium; Centre for Human Genetics, KU Leuven, Leuven, Belgium; Leuven Institute for Neuordegenerative Disorders (LIND), KU Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium
S Ali M Shariati
VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium; Centre for Human Genetics, KU Leuven, Leuven, Belgium; Leuven Institute for Neuordegenerative Disorders (LIND), KU Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium
Detlef Balschun
Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium
Bart De Strooper
VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium; Centre for Human Genetics, KU Leuven, Leuven, Belgium; Leuven Institute for Neuordegenerative Disorders (LIND), KU Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium; Institute of Neurology, University College London, London, United Kingdom
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.