Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory–inhibitory synapse formation in the mature cortex

Saurav Seshadri, Travis Faust, Koko Ishizuka, Kristen Delevich, Youjin Chung, Sun-Hong Kim, Martis Cowles, Minae Niwa, Hanna Jaaro-Peled, Toshifumi Tomoda, Cary Lai, E. S. Anton, Bo Li and Akira Sawa ()
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Saurav Seshadri: Johns Hopkins University
Travis Faust: Johns Hopkins University
Koko Ishizuka: Johns Hopkins University
Kristen Delevich: Watson School of Biological Sciences, Cold Spring Harbor Laboratory
Youjin Chung: Johns Hopkins University
Sun-Hong Kim: Johns Hopkins University
Martis Cowles: University of North Carolina
Minae Niwa: Johns Hopkins University
Hanna Jaaro-Peled: Johns Hopkins University
Toshifumi Tomoda: Beckman Research Institute of City of Hope
Cary Lai: Indiana University
E. S. Anton: University of North Carolina
Bo Li: Watson School of Biological Sciences, Cold Spring Harbor Laboratory
Akira Sawa: Johns Hopkins University

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Neuregulin-1 (NRG1) and its receptor ErbB4 influence several processes of neurodevelopment, but the mechanisms regulating this signalling in the mature brain are not well known. DISC1 is a multifunctional scaffold protein that mediates many cellular processes. Here we present a functional relationship between DISC1 and NRG1-ErbB4 signalling in mature cortical interneurons. By cell type-specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model, we demonstrate that DISC1 inhibits NRG1-induced ErbB4 activation and signalling. This effect is likely mediated by competitive inhibition of binding of ErbB4 to PSD95. Finally, we show that interneuronal DISC1 affects NRG1-ErbB4-mediated phenotypes in the fast spiking interneuron-pyramidal neuron circuit. Post-mortem brain analyses and some genetic studies have reported interneuronal deficits and involvement of the DISC1, NRG1 and ErbB4 genes in schizophrenia, respectively. Our results suggest a mechanism by which cross-talk between DISC1 and NRG1-ErbB4 signalling may contribute to these deficits.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10118

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DOI: 10.1038/ncomms10118

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