Dysregulated Expression of Neuregulin-1 by Cortical Pyramidal Neurons Disrupts Synaptic Plasticity

Arnav Agarwal, M Zhang, I Trembak-Duff, T Unterbarnscheidt, K Radyushkin, P Dibaj, DM de Souza, S Boretius, MM Brzozka, H Steffens, S Berning, Z Teng, MN Gummert, M Tantra, PC Guest, KI Willig, J Frahm, SW Hell, Sabine Bahn, MJ RossnerKA Nave, H Ehrenreich, WQ Zhang, MH Schwab

Research output: Contribution to journalArticleAcademic

78 Citations (Scopus)

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.
Original languageUndefined/Unknown
Pages (from-to)1130-1145
Number of pages16
JournalCell Reports
Volume8
Issue number4
DOIs
Publication statusPublished - 2014

Research programs

  • EMC ONWAR-01-94-01

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