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

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• The C57BL/6J mouse strain is a standard for genetic and behavioral research.
• The International Knockout Mouse Consortium utilizes a C57BL/6N substrain for creating knockout models.
• Differences between C57BL/6J and C57BL/6N substrains can impact experimental outcomes.

Purpose of the Study:

• To investigate the genetic basis for differential responses to psychostimulant drugs between C57BL/6J and C57BL/6N mouse substrains.
• To identify novel genes and genetic variants influencing cocaine and methamphetamine sensitivity.

Main Methods:

• Comparative behavioral analysis of C57BL/6J and C57BL/6N mice in response to cocaine and methamphetamine.
• Genetic mapping to identify the causative locus for altered drug response.
• Sanger sequencing and molecular analysis to pinpoint the specific mutation in Cytoplasmic FMRP interacting protein 2 (Cyfip2).
• Allelic deletion studies to confirm the role of the identified Cyfip2 variant.

Main Results:

• C57BL/6N mice exhibit significantly lower acute and sensitized responses to cocaine and methamphetamine compared to C57BL/6J mice.
• A single causative locus was identified, linked to a nonsynonymous mutation (serine to phenylalanine at position 968) in the Cyfip2 gene.
• This S968F mutation leads to destabilization of the CYFIP2 protein.
• Deletion of the mutant Cyfip2 allele in C57BL/6N mice restored typical acute and sensitized cocaine responses.

Conclusions:

• Cytoplasmic FMRP interacting protein 2 (Cyfip2) is a critical regulator of cocaine and methamphetamine response in mammals.
• The identified Cyfip2 S968F mutation is responsible for the observed behavioral differences between mouse substrains.
• Utilizing distinct mouse substrains is a valuable strategy for discovering novel genes and alleles that modulate complex behaviors.