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Nat Commun. 2015 Dec 11;6:10118. doi: 10.1038/ncomms10118.

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

Author information

1
Department of Psychiatry, Johns Hopkins University, 600 North Wolfe Street, Meyer 3-166A, Baltimore, Maryland 21287, USA.
2
Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21287, USA.
3
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
4
Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
5
Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
6
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.

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.

PMID:
26656849
PMCID:
PMC4682104
DOI:
10.1038/ncomms10118
[Indexed for MEDLINE]
Free PMC Article

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