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.
authors.affiliation: Department of Psychiatry, Johns Hopkins University, 600 North Wolfe Street, Meyer 3-166A, Baltimore, Maryland 21287, USA.
authors.forename: Saurav
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Faust
authors.affiliation: Department of Psychiatry, Johns Hopkins University, 600 North Wolfe Street, Meyer 3-166A, Baltimore, Maryland 21287, USA.
authors.forename: Koko
authors.initials: K
authors.lastname: Ishizuka
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Delevich
authors.affiliation: Department of Psychiatry, Johns Hopkins University, 600 North Wolfe Street, Meyer 3-166A, Baltimore, Maryland 21287, USA.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Department of Psychiatry, Johns Hopkins University, 600 North Wolfe Street, Meyer 3-166A, Baltimore, Maryland 21287, USA.
authors.forename: Sun-Hong
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Martis
authors.initials: M
authors.lastname: Cowles
authors.affiliation: Department of Psychiatry, Johns Hopkins University, 600 North Wolfe Street, Meyer 3-166A, Baltimore, Maryland 21287, USA.
authors.forename: Minae
authors.initials: M
authors.lastname: Niwa
authors.affiliation: Department of Psychiatry, Johns Hopkins University, 600 North Wolfe Street, Meyer 3-166A, Baltimore, Maryland 21287, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Jaaro-Peled
authors.affiliation: Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Tomoda
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
authors.forename: Cary
authors.initials: C
authors.lastname: Lai
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Anton
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex; D006801:Humans; D007395:Interneurons / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4