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 Aph1bdeficient 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.
Original language | English |
---|---|
Article number | e02196 |
Journal | eLife |
Volume | 2014 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2 Jun 2014 |
Externally published | Yes |
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ASJC Scopus subject areas
- Neuroscience(all)
- Medicine(all)
- Immunology and Microbiology(all)
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling. / Fazzari, Pietro; Snellinx, An; Sabanov, Victor; Ahmed, Tariq; Serneels, Lutgarde; Gartner, Annette; Shariati, S. Ali M; Balschun, Detlef; De Strooper, Bart.
In: eLife, Vol. 2014, No. 3, e02196, 02.06.2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling
AU - Fazzari, Pietro
AU - Snellinx, An
AU - Sabanov, Victor
AU - Ahmed, Tariq
AU - Serneels, Lutgarde
AU - Gartner, Annette
AU - Shariati, S. Ali M
AU - Balschun, Detlef
AU - De Strooper, Bart
PY - 2014/6/2
Y1 - 2014/6/2
N2 - 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 Aph1bdeficient 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.
AB - 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 Aph1bdeficient 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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UR - http://www.scopus.com/inward/citedby.url?scp=84904011196&partnerID=8YFLogxK
U2 - 10.7554/eLife.02196.001
DO - 10.7554/eLife.02196.001
M3 - Article
C2 - 24891237
AN - SCOPUS:84904011196
VL - 2014
JO - eLife
JF - eLife
SN - 2050-084X
IS - 3
M1 - e02196
ER -