FAAH genetic variation enhances fronto-amygdala function in mouse and human

Nat Commun. 2015 Mar 3:6:6395. doi: 10.1038/ncomms7395.


Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry and behaviour. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours. These results suggest a gain of function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.

Publication types

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

MeSH terms

  • Amidohydrolases / genetics*
  • Amidohydrolases / metabolism
  • Amygdala / physiology*
  • Animals
  • Blotting, Western
  • Extinction, Psychological / physiology
  • Fear / physiology
  • Frontal Lobe / physiology*
  • Gene Expression Regulation, Enzymologic / genetics*
  • Gene Knock-In Techniques / methods
  • Humans
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Magnetic Resonance Imaging
  • Mass Spectrometry
  • Mice
  • Polymorphism, Single Nucleotide / genetics*
  • Species Specificity


  • Amidohydrolases
  • fatty-acid amide hydrolase