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Cell Rep. 2014 Aug 21;8(4):1130-45. doi: 10.1016/j.celrep.2014.07.026. Epub 2014 Aug 14.

Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.

Author information

1
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.
2
Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, 48149 Muenster Germany.
3
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
4
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
5
Institute of Biotechnology, University of Cambridge, Cambridge CB2 1QT, UK.
6
Biomedizinische NMR Forschungs GmbH, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany.
7
Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
8
Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, 48149 Muenster Germany. Electronic address: wzhang@uni-muenster.de.
9
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany. Electronic address: schwab@em.mpg.de.

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.

PMID:
25131210
DOI:
10.1016/j.celrep.2014.07.026
[Indexed for MEDLINE]
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