Journal Article

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

Fazzari, Pietro, Gartner, Annette, De Strooper, Bart, Balschun, Detlef, Sabanov, Victor, Ahmed, Tariq, Snellinx, An, Shariati, S Ali M, Serneels, Lutgarde

2014

Overview

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. Schizophrenia affects around 1% of the world's population, with symptoms including hallucinations and delusions, apathy and cognitive impairments. Multiple genes and environmental factors interact to increase the risk of schizophrenia, making the causes of the disease—which can differ between individuals—difficult to disentangle. However, Schizophrenia is known to be associated with a reduction in the number of dendritic spines, the small protrusions that allow brain cells to receive inputs from other brain cells. One gene that has repeatedly been implicated in schizophrenia is neuregulin 1 (NRG1), which encodes a signalling protein with more than thirty different variants. One of these variants, type III NRG1, is located on the cell membrane. An enzyme called γ-secretase can cleave the 'tail' of this protein, which means that the tail becomes free to move to the nucleus of the cell, where it can alter the expression of genes. Fazzari et al. have now studied how different γ-secretases interact with type III NRG1 by using genetic techniques to remove a specific part of the enzymes in the brains of mice. The brain cells of these mutant mice contained fewer dendritic spines than mice with normal γ-secretases. However, the number of dendritic spines in the mutant mice could be restored by introducing γ-secretase. These results are consistent with a model in which mutations that remove the ability of γ-secretases to cleave NRG1 lead to some of the structural and functional changes in the brain that are associated with schizophrenia. An improved understanding of the properties of the various γ-secretases could also lead to the design of safer versions of drugs called γ-secretase modulators that are used to treat Alzheimer's disease.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Alzheimer Disease - genetics / Alzheimerand's disease / Amyloid Precursor Protein Secretases - metabolism / Animal models / Animals / Aph1b / Brain / Brain - metabolism / Dendritic spines / Disease Models, Animal / Electrophysiology / Endopeptidases - metabolism / Gamma-secretase / Gene Deletion / Gene Expression Regulation / Hippocampus / Hippocampus - embryology / Hippocampus - metabolism / Intracellular / Intracellular signalling / Mental disorders / Mice / Mice, Transgenic / Mutation / Neuregulin / Neuregulin 1 / Neuregulin-1 - metabolism / Neurons - metabolism / Neuroscience / NRG1 / Patch-Clamp Techniques / Pathogenesis / Plasmids / Risk factors / Schizophrenia / Schizophrenia - metabolism / Secretase / Signal Transduction / Synapses - metabolism / Synaptic plasticity / Synaptic transmission