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

Iva Dincheva, Andrew T. Drysdale, Catherine A. Hartley, David C. Johnson, Deqiang Jing, Elizabeth C. King, Stephen Ra, J. Megan Gray, Ruirong Yang, Ann Marie DeGruccio, Chienchun Huang, Benjamin F. Cravatt, Charles E. Glatt, Matthew N. Hill, B. J. Casey () and Francis S. Lee ()
Additional contact information
Iva Dincheva: Weill Cornell Medical College of Cornell University
Andrew T. Drysdale: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University
Catherine A. Hartley: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University
David C. Johnson: Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University
Deqiang Jing: Weill Cornell Medical College of Cornell University
Elizabeth C. King: Weill Cornell Medical College of Cornell University
Stephen Ra: Weill Cornell Medical College of Cornell University
J. Megan Gray: Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, University of Calgary
Ruirong Yang: Weill Cornell Medical College of Cornell University
Ann Marie DeGruccio: inGenious Targeting Laboratory
Chienchun Huang: Weill Cornell Medical College of Cornell University
Benjamin F. Cravatt: The Scripps Research Institute
Charles E. Glatt: Weill Cornell Medical College of Cornell University
Matthew N. Hill: Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, University of Calgary
B. J. Casey: Weill Cornell Medical College of Cornell University
Francis S. Lee: Weill Cornell Medical College of Cornell University

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7395

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