title: Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.
abstract: Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect.
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21025, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, 48149 Muenster Germany.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, 48149 Muenster Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Trembak-Duff
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Unterbarnscheidt
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Radyushkin
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Payam
authors.initials: P
authors.lastname: Dibaj
authors.affiliation: Institute of Biotechnology, University of Cambridge, Cambridge CB2 1QT, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martins de Souza
authors.affiliation: Biomedizinische NMR Forschungs GmbH, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Boretius
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Brzózka
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Steffens
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Berning
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, 48149 Muenster Germany.
authors.forename: Zenghui
authors.initials: Z
authors.lastname: Teng
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Maike N
authors.initials: MN
authors.lastname: Gummert
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Martesa
authors.initials: M
authors.lastname: Tantra
authors.affiliation: Institute of Biotechnology, University of Cambridge, Cambridge CB2 1QT, UK.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Guest
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Katrin I
authors.initials: KI
authors.lastname: Willig
authors.affiliation: Biomedizinische NMR Forschungs GmbH, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Frahm
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Hell
authors.affiliation: Institute of Biotechnology, University of Cambridge, Cambridge CB2 1QT, UK.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Moritz J
authors.initials: MJ
authors.lastname: Rossner
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, 48149 Muenster Germany. Electronic address: wzhang@uni-muenster.de.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany. Electronic address: schwab@em.mpg.de.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Schwab
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000502:physiology; D002465:Cell Movement; D003213:Conditioning, Psychological; D049229:Dendritic Spines / Q000502:physiology; D005239:Fear; D005260:Female; D015870:Gene Expression; D007395:Interneurons / Q000502:physiology; D008297:Male; D008822:Mice, Transgenic; D009415:Nerve Net; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity; D017966:Pyramidal Cells / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D020890:Neuregulin-1; C490581:Nrg1 protein, mouse