C57BL/6N Mutation in Cytoplasmic FMRP interacting protein 2 Regulates Cocaine Response

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Science  20 Dec 2013:
Vol. 342, Issue 6165, pp. 1508-1512
DOI: 10.1126/science.1245503

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Not All Mice Are Equal

Different laboratories often use different strains of inbred animals, but one cannot make behavioral comparisons and assume that their reaction to interventions will necessarily be similar. Kumar et al. (p. 1508) have detected differences in cocaine response between the widely used C57BL/6N and C57BL/6J mouse strains and used quantitative trait locus analysis to identify a mutation in an inducible gene, Cyfip, that interacts with the Fragile X protein (FMRP) to regulate sensitivity and sensitization to cocaine through regulation of neuronal connectivity.


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.

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