| First Author | Dincheva I | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 6395 | PubMed ID | 25731744 |
| Mgi Jnum | J:221783 | Mgi Id | MGI:5641561 |
| Doi | 10.1038/ncomms7395 | Citation | Dincheva I, et al. (2015) FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat Commun 6:6395 |
| abstractText | 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. |
