Iva Dincheva 1 , 2 , Andrew T. Drysdale 3 , Catherine A. Hartley 3 , David C. Johnson 3 , Deqiang Jing 1 , Elizabeth C. King 1 , 2 , Stephen Ra 1 , Megan Gray 4 , Ruirong Yang 1 , Ann Marie DeGruccio 5 , Chienchun Huang 1 , Benjamin F. Cravatt 6 , Charles E. Glatt 1 , Matthew N. Hill 4 , B. J. Casey 1 , 2 , † , Francis S. Lee 1 , 2 , 3 , †
03 March 2015
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 behavior. 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 behaviors. 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.