Endocannabinoids and the FAAH polymorphism

Using a vertically integrated approach in parallel mouse-human studies to we have analyzed a common human genetic variant in the endocannabinoid system, which highlights the capacity to study molecular defects in plasticity genes, and link them to circuit-level and behavioral phenotypes. 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. We have shown that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemistry, 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 findings bridge an important translational gap between the mouse and human.