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

Academic Article
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Overview

authors

  • Dincheva, I.
  • Drysdale, A. T.
  • Hartley, C. A.
  • Johnson, D. C.
  • Jing, D.
  • King, E. C.
  • Ra, S.
  • Gray, J. M.
  • Yang, R.
  • DeGruccio, A. M.
  • Huang, C.
  • Cravatt, Benjamin
  • Glatt, C. E.
  • Hill, M. N.
  • Casey, B. J.
  • Lee, F. S.

publication date

  • March 2015

journal

  • Nature Communications  Journal

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.

subject areas

  • Amidohydrolases
  • 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
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Identity

PubMed Central ID

  • PMC4351757

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms7395

PubMed ID

  • 25731744
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Additional Document Info

start page

  • 6395

volume

  • 6

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