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, Akira Sawa

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number10118
JournalNature Communications
Volume6
DOIs
StatePublished - Dec 11 2015

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Neuregulin-1
synapses
cortexes
genes
Synapses
brain
schizophrenia
spiking
phenotype
neurons
mice
activation
Interneurons
proteins
modulation
Brain
Genes
cells
Competitive Binding
Pyramidal Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. / Seshadri, Saurav; Faust, Travis; Ishizuka, Koko; Delevich, Kristen; Chung, Youjin; Kim, Sun-Hong; Cowles, Martis; Niwa, Minae; Jaaro-Peled, Hanna; Tomoda, Toshifumi; Lai, Cary; Anton, E. S.; Li, Bo; Sawa, Akira.

In: Nature Communications, Vol. 6, 10118, 11.12.2015.

Research output: Contribution to journalArticle

Seshadri, Saurav ; Faust, Travis ; Ishizuka, Koko ; Delevich, Kristen ; Chung, Youjin ; Kim, Sun-Hong ; Cowles, Martis ; Niwa, Minae ; Jaaro-Peled, Hanna ; Tomoda, Toshifumi ; Lai, Cary ; Anton, E. S. ; Li, Bo ; Sawa, Akira. / Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. In: Nature Communications. 2015 ; Vol. 6.
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