Neuregulin-3 in the Mouse Medial Prefrontal Cortex Regulates Impulsive Action

Background: A deficit in impulse control is a prominent, heritable symptom in several psychiatric disorders, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia. Here, we aimed to identify genes regulating impulsivity, specifically of impulsive action, in mice. Methods: Using the widely used 5-choice serial reaction time task, we measured impulsive action in 1) a panel of 41 BXD recombinant inbred strains of mice (n = 13.7 +/- .8 per strain; n = 654 total) to detect underlying genetic loci; 2) congenic mice (n = 23) to replicate the identified locus; 3) mice overexpressing the Nrg3 candidate gene in the medial prefrontal cortex (n = 21); and 4) a Nrg3 loss-of-function mutant (n = 59) to functionally implicate the Nrg3 candidate gene in impulsivity. Results: Genetic mapping of impulsive action in the BXD panel identified a locus on chromosome 14 (34.5-41.4 Mb), syntenic with the human 10q22-q23 schizophrenia-susceptibility locus. Congenic mice carrying the impulsivity locus (Impu1) confirmed its influence on impulsive action. Increased impulsivity was associated with increased Nrg3 gene expression in the medial prefrontal cortex (mPFC). Viral overexpression of Nrg3 in the mPFC increased impulsivity, whereas a constitutive Nrg3 loss-of-function mutation decreased it. Conclusions: The causal relation between Nrg3 expression in the mPFC and level of impulsive action shown here provides a mechanism by which polymorphism in NRG3 in humans contributes to a specific cognitive deficit seen in several psychiatric diseases, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia.