FAAH genetic variation enhances fronto-amygdala function in mouse and human.
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.
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.
Iva
I
Dincheva
Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Andrew T
AT
Drysdale
Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Catherine A
CA
Hartley
Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
David C
DC
Johnson
Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Deqiang
D
Jing
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.
Elizabeth C
EC
King
Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Stephen
S
Ra
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.
J Megan
JM
Gray
Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Ruirong
R
Yang
inGenious Targeting Laboratory, 2200 Smithtown Avenue, Ronkonkoma, New York 11779, USA.
Ann Marie
AM
DeGruccio
Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Chienchun
C
Huang
Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Benjamin F
BF
Cravatt
Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Charles E
CE
Glatt
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.
Matthew N
MN
Hill
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.
B J
BJ
Casey
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.
Francis S
FS
Lee
D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D000679:Amygdala / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology; D005625:Frontal Lobe / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D055879:Gene Knock-In Techniques / Q000379:methods; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D013058:Mass Spectrometry; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013045:Species Specificity; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000099252:Fatty Acid Amide Hydrolases