C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response

Science. 2013 Dec 20;342(6165):1508-12. doi: 10.1126/science.1245503.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Substitution
  • Animals
  • Central Nervous System Stimulants / administration & dosage
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / genetics*
  • Cocaine-Related Disorders / psychology*
  • Drug-Seeking Behavior*
  • Methamphetamine / administration & dosage
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Phenylalanine / genetics
  • Polymorphism, Single Nucleotide
  • Psychomotor Performance / drug effects
  • Quantitative Trait Loci
  • Serine / genetics


  • Adaptor Proteins, Signal Transducing
  • Central Nervous System Stimulants
  • Cyfip2 protein, mouse
  • Nerve Tissue Proteins
  • Methamphetamine
  • Serine
  • Phenylalanine
  • Cocaine