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.
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam; Sylics (Synaptologics BV), Amsterdam, The Netherlands.
Maarten
M
Loos
Department of Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Thomas
T
Mueller
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam.
Yvonne
Y
Gouwenberg
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam; Sylics (Synaptologics BV), Amsterdam, The Netherlands.
Ruud
R
Wijnands
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam; Sylics (Synaptologics BV), Amsterdam, The Netherlands.
Rolinka J
RJ
van der Loo
Department of Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Carmen
C
Birchmeier
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam.
August B
AB
Smit
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam. Electronic address: s.spijker@vu.nl.
Sabine
S
Spijker
D000818:Animals; D002755:Choice Behavior / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007175:Impulsive Behavior / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020880:Neuregulins; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000473:pathology*; D040641:Quantitative Trait Loci; D011930:Reaction Time / Q000235:genetics; D018709:Statistics, Nonparametric
D047908:Intracellular Signaling Peptides and Proteins; D020880:Neuregulins; C108113:Nrg3 protein, mouse; D020319:Oligodeoxyribonucleotides, Antisense; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
5CSRTT; Behavior; Erbb4; impulsivity; inhibitory control; neuregulin