BDNF Val66Met genotype and adolescent glucocorticoid treatment induce sex-specific disruptions to fear extinction and amygdala GABAergic interneuron expression in mice.

Background: The BDNF Val66Met single nucleotide polymorphism has been implicated in stress sensitivity and Post-Traumatic Stress Disorder (PTSD) risk. We previously reported that chronic young-adult stress hormone treatment enhanced fear memory in adult BDNF mice with the Met/Met genotype. This study aimed to extend this work to fear extinction learning, spontaneous recovery of fear, and neurobiological correlates in the amygdala.

Methods: Male and female Val/Val and Met/Met mice received corticosterone in their drinking water during late adolescence to model chronic stress. Following a 2-week recovery period, the mice underwent fear conditioning and extinction training. Immunofluorescent labelling was used to assess density of three interneuron subtypes; somatostatin, parvalbumin and calretinin, within distinct amygdala nuclei.

Results: No significant effects of genotype, treatment or sex were found for fear learning. However, adolescent CORT treatment selectively abolished fear extinction of female Met/Met mice. No effect of genotype, sex, or treatment was observed for spontaneous recovery of fear. Significant main effects of genotype and CORT emerged for somatostatin and calretinin cell density, again in females only, further supporting sex-specific effects of the Met/Met genotype and chronic CORT exposure.

Conclusion: BDNF Val66Met genotype interacts with chronic adolescent stress hormone exposure to abolish fear extinction in female Met/Met mice in adulthood. This effect was associated with female-specific interneuron dysfunction induced by either genotype or stress hormone exposure, depending on the interneuron subtype. These data provide biological insight into the role of BDNF in sex differences in sensitivity to stress and vulnerability to stress-related disorders in adulthood.