Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance

Abstract

BDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val66met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val66met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val66met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.

Figure 1.

Statistical parametric maps showing significant engagement of the hippocampal formation (hippocampus and parahippocampal gyrus) during encoding and retrieval. BOLD fMRI responses in the posterior hippocampal formation are shown overlaid onto averaged structural MRIs in the axial, coronal, and sagittal plane. Blue cross-hairs are centered on the left hippocampal formation clusters during encoding and retrieval that contributed maximally to the observed variance in memory performance (see Regression analysis in Materials and Methods). a, Talairach coordinates and voxel-level statistics for the maximal voxel in the left and right hippocampal formation during encoding are x =-25 mm; y =-44 mm; z = -10 mm; cluster size = 42 voxels; voxel-level corrected p < 0.001; Z score = 5.59; and x = 22 mm; y = -48 mm; z = -10 mm; cluster size = 60 voxels; voxel-level corrected p < 0.001; Z score = 7.24, respectively. b, Talairach coordinates and voxel-level statistics for the maximal voxel in the left and right HF during retrieval are x = -25 mm; y = -44 mm; z = -10 mm; cluster size = 36 voxels; voxel-level corrected p < 0.001; Z score = 6.32; and x = 22 mm; y =-48 mm; z = -10 mm; cluster size = 64 voxels; voxel-level corrected p < 0.001; Z score = 7.08, respectively.

Figure 2.

Genotype-based parametric comparisons showing significantly greater hippocampal activity in the Val group versus the Met group during both encoding and retrieval. BOLD fMRI responses in the posterior hippocampal formation are shown overlaid onto averaged structural MRIs in the coronal and sagittal plane. a, Talairach coordinates and voxel-level statistics for the maximal voxels in the right hippocampus and parahippocampal gyrus exhibiting Val greater than Met activity during encoding: x = 30 mm; y =-19 mm; z = -12 mm; cluster size = 5 voxels; voxel-level corrected p = 0.047; Z score = 1.91; and x = 22 mm; y = -44 mm; z = -6 mm; cluster size = 6 voxels; voxel-level corrected p = 0.043; Z score = 1.97, respectively. b, Talairach coordinates and voxel-level statistics for the maximal voxels in the left and right parahippocampal gyrus exhibiting Val greater than Met activity during retrieval: x = -30 mm; y = -44 mm; z = -2 mm; cluster size = 3 voxels; voxel-level corrected p = 0.046; Z score = 1.87; and x = 22 mm; y =-48 mm; z = -6 mm; cluster size = 7 voxels; voxel-level corrected p = 0.035; Z score = 2.45, respectively.