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

doi:10.1038/ncomms10118

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Article number	10118
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms10118
State	Published - Dec 11 2015

ASJC Scopus subject areas

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

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Seshadri, S., Faust, T., Ishizuka, K., Delevich, K., Chung, Y., Kim, S. H., Cowles, M., Niwa, M., Jaaro-Peled, H., Tomoda, T., Lai, C., Anton, E. S., Li, B., & Sawa, A. (2015). Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. Nature communications, 6, Article 10118. https://doi.org/10.1038/ncomms10118

@article{21b4170ab2924856866d1bc0f3cfa692,

title = "Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex",

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.",

author = "Saurav Seshadri and Travis Faust and Koko Ishizuka and Kristen Delevich and Youjin Chung and Kim, {Sun Hong} and Martis Cowles and Minae Niwa and Hanna Jaaro-Peled and Toshifumi Tomoda and Cary Lai and Anton, {E. S.} and Bo Li and Akira Sawa",

note = "Funding Information: We thank Yukiko L. Lema for preparing the figures and organizing the manuscript. This work was supported by USPHS grants of MH-084018 (A.S.), MH-094268 Silvo O. Conte center (A.S.), MH-069853 (A.S.), MH-085226 (A.S.), MH-088753 (A.S.), MH-092443 (A.S.), MH-105660 (A.S., K.I.) and grants from the following foundations: Stanley (A.S.), RUSK (A.S.), S-R foundations (A.S.), NARSAD (K.I., A.S.) and Maryland Stem Cell Research Fund (K.I., A.S.). Additional support was provided by National Research Service Award fellowship F31MH081475 (S.S.).",

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doi = "10.1038/ncomms10118",

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T1 - Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex

AU - Seshadri, Saurav

AU - Faust, Travis

AU - Ishizuka, Koko

AU - Delevich, Kristen

AU - Chung, Youjin

AU - Kim, Sun Hong

AU - Cowles, Martis

AU - Niwa, Minae

AU - Jaaro-Peled, Hanna

AU - Tomoda, Toshifumi

AU - Lai, Cary

AU - Anton, E. S.

AU - Li, Bo

AU - Sawa, Akira

N1 - Funding Information: We thank Yukiko L. Lema for preparing the figures and organizing the manuscript. This work was supported by USPHS grants of MH-084018 (A.S.), MH-094268 Silvo O. Conte center (A.S.), MH-069853 (A.S.), MH-085226 (A.S.), MH-088753 (A.S.), MH-092443 (A.S.), MH-105660 (A.S., K.I.) and grants from the following foundations: Stanley (A.S.), RUSK (A.S.), S-R foundations (A.S.), NARSAD (K.I., A.S.) and Maryland Stem Cell Research Fund (K.I., A.S.). Additional support was provided by National Research Service Award fellowship F31MH081475 (S.S.).

PY - 2015/12/11

Y1 - 2015/12/11

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms10118

DO - 10.1038/ncomms10118

M3 - Article

C2 - 26656849

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SN - 2041-1723

VL - 6

JO - Nature communications

JF - Nature communications

M1 - 10118

ER -

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

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