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

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

Author information

1
1] Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA [2] Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
2
Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
3
Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
4
Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy &Psychiatry, University of Calgary, 3330 Hospital Drive NW, Calgary AB Canada T2N4N1.
5
inGenious Targeting Laboratory, 2200 Smithtown Avenue, Ronkonkoma, New York 11779, USA.
6
Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
7
1] Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA [2] Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA [3] Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.

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 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.

PMID:
25731744
PMCID:
PMC4351757
DOI:
10.1038/ncomms7395
[Indexed for MEDLINE]
Free PMC Article

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