Variant Brain-Derived Neurotrophic Factor Val66Met Polymorphism Alters Vulnerability to Stress and Response to Antidepressants

Abstract

Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found human BDNF Val66Met (BDNFMet) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNFMet polymorphism and stress are unclear. We found that heterozygous BDNF+/Met mice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared with WT mice after 7 d restraint stress. Moreover, BDNF+/Met miceexhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors in BDNF+/Met mice could be selectively rescued by acute administration of desipramine but not fluoxetine. These data indicate selective behavioral, molecular, and structural deficits resulting from the interaction between stress and the human genetic BDNFMet polymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects on BDNF+/Met mice, suggesting that specific classes of antidepressant may be a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF.

BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity

“…Given that the Val66Met genotype determines stress sensitivity, 26 and that in healthy samples both mild social stress 27 and childhood abuse 28 result in an increase in the expression of psychosis-related symptom expression in BDNF 66Met allele carriers, a secondary aim was to explore whether a chronic corticosterone (CORT) treatment administered in late adolescence/young adulthood, a critical period associated with the psychosis prodrome, may interact with BDNF genotype to determine adult PPI. ), 2 treatment groups (CORT and control) and 2 sexes (male and female).…”

The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice

“…During the MWM test, water acts as an aversive stimulus that reinforces the mice to enter the platform, hence MWM tasks are stressful for mice (Harrison et al 2009) and stress has been shown to affect learning and memory performance (Francis et al 1995;Roozendaal et al 2009;Yu et al 2012). To evaluate escape and search strategies (Harrison et al 2006) in the absence of an aversive stimulus we used a circular Barnes maze, which was modified to test for spatial learning capabilities in mice (Koopmans et al 2003).…”

Translational Findings on Brain-Derived Neurotrophic Factor and Anxiety: Contributions from Basic Research to Clinical Practice

“…In addition, the BDNF polymorphism is believed to be associated with responsiveness of the hypothalamic-pituitary-adrenal axis to psychological stress characterized by individual differences in stress regulation and possibly genetic vulnerability to stress-related disorders [75,76,77,78]. …”

“…Administration of fluoxetine, an antidepressant for which one postulated mechanism of action involves increasing BDNF levels, the BDNF Met/Met mice showed decreased anxiety-related behaviors in the open field and in the novelty-induced hypophagia tests. The authors report that only the homozygous mice exhibited anxiety, and that although a correlation between this animal model and heterozygous individuals cannot be made, it can be suggested that genetic, as well as environmental influences, might be required for this SNP to influence psychiatric pathology [71,75]. …”