A genetic variant BDNF polymorphism alters extinction learning in both mouse and human

Abstract

Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.

Figure 1. Altered extinction in mice and humans with BDNF Val66Met

Impaired extinction in Met allele carriers (Val/Met and Met/Met) as a function of time in 68 mice (A) and 72 humans (B) as indexed by percent time freezing in mice and skin conductance response (SCR) in humans to the conditioned stimulus when it was no longer paired with the aversive stimulus. All results are presented as a mean ± SEM. *p < 0.01, Student’s t test. **p < 0.02, Student’s t test. VV = Val/Val; VM = Val/Met; MM= Met/Met.

Figure 2. Impaired learning of neutral cue in human Met allele carriers

Elevated skin conductance response (SCR) to the cue never paired with the aversive stimulus during fear conditioning as a function of time in Met allele carriers (VM) relative to nonMet allele carriers (VV). All results are presented as a mean ± SEM. *p < 0.001, Student’s t test. VV = Val/Val; VM = Val/Met.

Figure 3. Neural circuitry of the behavioral effect of BDNF Val66Met during extinction

(A) Average percent freezing during extinction by genotype in 68 mice. (B) Average skin conductance response (SCR) during extinction by genotype in 72 humans. (C) Brain activity as indexed by percent change in MR signal during extinction in the ventromedial prefrontal cortex (vmPFC) by genotype (xyz = −4, 24, 3), with Met allele carriers having significantly less activity than Val/Val homozygotes [VM < VV = blue], image threshold p < 0.05, corrected. (D) Genotypic differences in left amygdala activity during extinction (xyz = −25, 2, −20) in 70 humans, with Met allele carriers having significantly greater activity than Val/Val homozygotes [VM > VV = orange], image threshold p < 0.05, corrected. *p < 0.05. **MM were included in the analysis with VM, but plotted separately to see dose response. All results are presented as a mean ± SEM. VV = Val/Val; VM = Val/Met; MM = Met/Met; MR = magnetic resonance.