title: C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response.
abstract: The inbred mouse C57BL/6J is the reference strain for genome sequence and for most behavioral and physiological phenotypes. However, the International Knockout Mouse Consortium uses an embryonic stem cell line derived from a related C57BL/6N substrain. We found that C57BL/6N has a lower acute and sensitized response to cocaine and methamphetamine. We mapped a single causative locus and identified a nonsynonymous mutation of serine to phenylalanine (S968F) in Cytoplasmic FMRP interacting protein 2 (Cyfip2) as the causative variant. The S968F mutation destabilizes CYFIP2, and deletion of the C57BL/6N mutant allele leads to acute and sensitized cocaine-response phenotypes. We propose that CYFIP2 is a key regulator of cocaine response in mammals and present a framework to use mouse substrains to identify previously unknown genes and alleles regulating behavior.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Kyungin
authors.initials: K
authors.lastname: Kim
authors.forename: Chryshanthi
authors.initials: C
authors.lastname: Joseph
authors.forename: Saïd
authors.initials: S
authors.lastname: Kourrich
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoo
authors.forename: Hung Chung
authors.initials: HC
authors.lastname: Huang
authors.forename: Martha H
authors.initials: MH
authors.lastname: Vitaterna
authors.forename: Fernando Pardo-Manuel
authors.initials: FP
authors.lastname: de Villena
authors.forename: Gary
authors.initials: G
authors.lastname: Churchill
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000523:psychology*; D058999:Drug-Seeking Behavior; D008694:Methamphetamine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010649:Phenylalanine / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011597:Psychomotor Performance / Q000187:drug effects; D040641:Quantitative Trait Loci; D012694:Serine / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000697:Central Nervous System Stimulants; C529497:Cyfip2 protein, mouse; D009419:Nerve Tissue Proteins; D008694:Methamphetamine; D012694:Serine; D010649:Phenylalanine; D003042:Cocaine