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

Iva Dincheva,J Megan Gray,Charles E Glatt,Ruirong Yang,Chienchun Huang,Francis S Lee,Matthew N Hill,Ann Marie Degruccio,David C Johnson,Benjamin F Cravatt,Andrew T Drysdale,B J Casey,Catherine A Hartley,Stephen Ra,Deqiang Jing,Elizabeth C King

doi:10.1038/ncomms7395

Abstract

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.

Highlights

Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms
We show that a single-nucleotide polymorphism (SNP) in the fatty acid amide hydrolase (FAAH) gene of the endocannabinoid system has parallel molecular, neural and behavioural effects in both humans and mice engineered to express the variant human allele, filling an important translational gap
The FAAH C385A SNP enhances endogenous cannabinoid (eCB) signalling by reducing steady-state levels of FAAH protein, which leads to elevated AEA levels[7,8,9]

Summary

Introduction

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. 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. We show that a single-nucleotide polymorphism (SNP) in the fatty acid amide hydrolase (FAAH) gene of the endocannabinoid system has parallel molecular, neural and behavioural effects in both humans and mice engineered to express the variant human allele, filling an important translational gap. We describe the development of a knock-in mouse that expresses the variant A (threonine) allele of the FAAH polymorphism in place of the conserved ancestral C (proline) allele, enabling the demonstration of parallel molecular, circuit-level and behavioural phenotypes in humans and in the knock-in mice carrying this variant

Methods

Results

Conclusion