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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.

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


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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