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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournaleLife
Volume3
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Neuregulin-1
Amyloid Precursor Protein Secretases
Schizophrenia
Dendritic Spines
Neuronal Plasticity
Synaptic Transmission
Plasticity
Rodentia
Brain
Genes
Mutation
Processing
Experiments

Keywords

  • Alzheimerand's disease
  • Aph1b
  • Gamma-secretase
  • mouse
  • neuroscience
  • NRG1
  • schizophrenia

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Fazzari, P., Snellinx, A., Sabanov, V., Ahmed, T., Serneels, L., Gartner, A., ... De Strooper, B. (2014). Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling. eLife, 3. https://doi.org/10.7554/eLife.02196

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. 3, 2014.

Research output: Contribution to journalArticle

Fazzari, P, Snellinx, A, Sabanov, V, Ahmed, T, Serneels, L, Gartner, A, Shariati, SAM, Balschun, D & De Strooper, B 2014, 'Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling', eLife, vol. 3. https://doi.org/10.7554/eLife.02196
Fazzari, Pietro ; Snellinx, An ; Sabanov, Victor ; Ahmed, Tariq ; Serneels, Lutgarde ; Gartner, Annette ; Shariati, S. Ali M ; Balschun, Detlef ; De Strooper, Bart. / Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling. In: eLife. 2014 ; Vol. 3.
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