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

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Cross-species studies are crucial for translational research, requiring consistent mechanisms and phenotypes.
• Fatty acid amide hydrolase (FAAH) is the primary enzyme metabolizing anandamide, a key endocannabinoid.
• A common human FAAH polymorphism (C385A; rs324420) affects enzyme activity and anandamide levels.

Purpose of the Study:

• To develop a knock-in mouse model that recapitulates the human FAAH C385A mutation.
• To investigate the parallel biochemical, neurocircuitry, and behavioral effects in mice and human carriers.
• To explore the translational implications for FAAH inhibitors and anxiety treatments.

Main Methods:

• Developed a knock-in mouse model for the human FAAH C385A mutation.
• Compared biochemical, neurocircuitry, and behavioral phenotypes between knock-in mice and human variant allele carriers.
• Assessed FAAH expression, fronto-amygdala connectivity, fear extinction learning, and anxiety-like behaviors.

Main Results:

• The knock-in mouse and human carriers exhibited reduced FAAH expression associated with the variant allele.
• This genetic variant selectively enhanced fronto-amygdala connectivity and fear extinction learning.
• Anxiety-like behaviors were decreased in individuals with the FAAH variant allele.

Conclusions:

• The FAAH C385A variant confers a gain of function in fear regulation.
• This model bridges a translational gap between mouse and human studies.
• Findings may guide the personalized application of FAAH inhibitors and exposure therapies for anxiety symptoms.