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.

Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation

“…Egan et al 32 identified decreased NAA, a putative measure of neuronal integrity, in the hippocampus and abnormal hippocampal activation as assessed via functional magnetic resonance imaging (fMRI) in association with the met allele. Similarly, in an fMRI study that assessed the relationship between BDNF val66met genotype and hippocampal activity during episodic memory processing, Hariri et al 34 reported that met carriers exhibited decreased hippocampal engagement compared to val/val homozygotes during both encoding and retrieval of information. The results of our study thus extend the findings of Egan et al 32 and Hariri et al 34 by implicating a role for genetic variation in the val66met polymorphism in association with hippocampal volume.…”

“…Prior work suggests that the BDNF val66met polymorphism may be associated with impaired cognitive functioning and, in particular, worse memory functioning in humans. Specifically, healthy humans homozygous for the val allele exhibit better memory functioning 32 greater mean performance IQ, 33 higher hippocampal N-acetylaspartate (NAA) 32 and increased functional activity within the hippocampus during a memory task 34 compared to met carriers. Although hippocampal volume is significantly heritable, 35,36 the relationship between polymorphisms in the BDNF gene and hippocampal structure has not been well-studied.…”

“…In this study, we investigated the relationship between the val66met polymorphism and volume of the hippocampal formation in patients experiencing a first-episode of schizophrenia and healthy volunteers. Based on previously published studies, 32,34 we hypothesized that (1) individuals who are val/met heterozygotes would have smaller volumes of the hippocampal formation compared to val/val homozygotes and (2) that these effects would be more pronounced among patients compared to healthy volunteers given previous evidence of both hippocampal structural pathology and BDNF involvement in schizophrenia.…”

Brain‐derived neurotropic factor polymorphisms, traumatic stress, mild traumatic brain injury, and combat exposure contribute to postdeployment traumatic stress

“…BDNF has a role in activity‐dependent neural plasticity processes of the hippocampus and amygdala, implicated in long‐term learning and memory (Hariri et al. 2003; Andero and Ressler 2012; Mahan and Ressler 2012). In one study, low BDNF serum levels were associated with PTSD, while another reported no relationship to PTSD in victims of urban violence (Valente et al.…”

No gene-by-environment interaction of BDNF Val66Met polymorphism and childhood maltreatment on anxiety sensitivity in a mixed race adolescent sample

“…BDNF is widely expressed in the hippocampus and cerebral cortex (Hofer, Pagliusi, Hohn, Leibrock, & Barde, 1990; Huang & Reichardt, 2001) and enhances hippocampal long-term potentiation (Figurov, Pozzo-Miller, Olafsson, Wang, & Lu, 1996) associated with both memory and learning efficiency (Hariri et al, 2003; Yamada, Mizuno, & Nabeshima, 2002). The gene encoding BDNF contains a functional single-nucleotide polymorphism (SNP) resulting in a valine (val) to methionine (met) substitution at amino acid 66 ( Val66Met , rs6265) in the 5ʹ pro-BDNF domain (Egan et al, 2003).…”