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

TitleFAAH genetic variation enhances fronto-amygdala function in mouse and human.
Publication TypeJournal Article
Year of Publication2015
AuthorsDincheva I, Drysdale AT, Hartley CA, Johnson DC, Jing D, King EC, Ra S, J Gray M, Yang R, DeGruccio AMarie, Huang C, Cravatt BF, Glatt CE, Hill MN, Casey BJ, Lee FS
JournalNat Commun
Volume6
Pagination6395
Date Published2015 Mar 03
ISSN2041-1723
KeywordsAmidohydrolases, Amygdala, Animals, Blotting, Western, Extinction, Psychological, Fear, Frontal Lobe, Gene Expression Regulation, Enzymologic, Gene Knock-In Techniques, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Magnetic Resonance Imaging, Mass Spectrometry, Mice, Polymorphism, Single Nucleotide, Species Specificity
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.

DOI10.1038/ncomms7395
Alternate JournalNat Commun
PubMed ID25731744
PubMed Central IDPMC4351757
Grant ListMH079513 / MH / NIMH NIH HHS / United States
GM07739 / GM / NIGMS NIH HHS / United States
P50 MH079513 / MH / NIMH NIH HHS / United States
EY007138 / EY / NEI NIH HHS / United States
R01 NS052819 / NS / NINDS NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
MH060478 / MH / NIMH NIH HHS / United States
NS052819 / NS / NINDS NIH HHS / United States
DA017259 / DA / NIDA NIH HHS / United States
P01 DA017259 / DA / NIDA NIH HHS / United States
T32 EY007138 / EY / NEI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
R25 MH060478 / MH / NIMH NIH HHS / United States