j.celrep.2014.07.026 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). SUMMARY 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 mu-tants 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 over-expression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced ex-citatory-inhibitory neurotransmission, reduced syn-aptic 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 neurotransmis-sion in the cortex. Our data provide a potential path-omechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect. INTRODUCTION