TY - JOUR
T1 - Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity
AU - Agarwal, Amit
AU - Zhang, Mingyue
AU - Trembak-Duff, Irina
AU - Unterbarnscheidt, Tilmann
AU - Radyushkin, Konstantin
AU - Dibaj, Payam
AU - Martins de Souza, Daniel
AU - Boretius, Susann
AU - Brzózka, Magdalena M.
AU - Steffens, Heinz
AU - Berning, Sebastian
AU - Teng, Zenghui
AU - Gummert, Maike N.
AU - Tantra, Martesa
AU - Guest, Peter C.
AU - Willig, Katrin I.
AU - Frahm, Jens
AU - Hell, Stefan W.
AU - Bahn, Sabine
AU - Rossner, Moritz J.
AU - Nave, Klaus Armin
AU - Ehrenreich, Hannelore
AU - Zhang, Weiqi
AU - Schwab, Markus H.
N1 - Funding Information:
We thank A. Fahrenholz and M. Floerl for excellent technical assistance. We also thank C. Casper and D. Flemming for help with animal husbandry. We thank C. Birchmeier for providing conditional NRG1 mutant mice, R. Klein for CamKII-Cre mice, K. Jones for EmxI-Cre mice, F. Kirchhoff for Thy1.2-YFP mice, and H. Monyer for PV-GFP mice. We thank N. Brose, S. Papiol, S. Wichert, and members of the Department of Neurogenetics for helpful discussions. A.A. is supported by a Postdoctoral Fellowship from the National Multiple Sclerosis Society. W.Z. is supported by the IZKF of the University of Münster Medical School (Zha3-005-14). M.J.R. and M.M.B. were supported by the Deutsche Forschungsgemeinschaft (Klinische Forschergruppe [KFO] 241: RO 4076/1-1). S.W.H., W.Z., M.H.S., and K.-A.N. acknowledge grant support from the Deutsche Forschungsgemeinschaft (DFG Research Center Molecular Physiology of the Brain [CMPB] and SFB TRR58 to W.Z.). M.H.S. is supported by a Heisenberg fellowship from the Deutsche Forschungsgemeinschaft. K.-A.N. holds an ERC Advanced Grant.
PY - 2014/8/21
Y1 - 2014/8/21
N2 - Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated ordecreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions invivo, 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.
AB - Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated ordecreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions invivo, 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.
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U2 - 10.1016/j.celrep.2014.07.026
DO - 10.1016/j.celrep.2014.07.026
M3 - Article
C2 - 25131210
AN - SCOPUS:84908356739
SN - 2211-1247
VL - 8
SP - 1130
EP - 1145
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -