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.
Key Words
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Article info
Publication history
Published online: February 26, 2014
Accepted:
February 11,
2014
Received in revised form:
January 24,
2014
Received:
August 25,
2013
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
