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

Amit Agarwal, Mingyue Zhang, Irina Trembak-Duff, Tilmann Unterbarnscheidt, Konstantin Radyushkin, Payam Dibaj, Daniel Martins de Souza, Susann Boretius, Magdalena M. Brzózka, Heinz Steffens, Sebastian Berning, Zenghui Teng, Maike N. Gummert, Martesa Tantra, Peter C. Guest, Katrin I. Willig, Jens Frahm, Stefan W. Hell, Sabine Bahn, Moritz J. RossnerKlaus Armin Nave, Hannelore Ehrenreich, Weiqi Zhang, Markus H. Schwab

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1130-1145
Number of pages16
JournalCell Reports
Volume8
Issue number4
DOIs
StatePublished - Aug 21 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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