Impact of the BDNF Val66Met polymorphism on cognition: implications for behavioral genetics

Abstract

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family and is implicated as a modulator of neuronal survival and differentiation, synaptic plasticity, and higher order cognitive functions such as learning and memory. A common single-nucleotide polymorphism (SNP) has been identified in the human BDNF gene (BDNF Val66Met) that leads to decreased BDNF secretion and impairments in specific forms of learning in humans. To better understand the impact of this SNP on biological function, the authors generated a mouse model containing the BDNF Met allele, which they found to replicate the key phenotypes observed in humans and provided further insight into the functional impact of this SNP in vivo. They used a "bottom-up" approach to study the BDNF SNP, which provided external validation in biologically less complex, genetically uniform systems, which minimized the variability inherent in human studies. In this review, the authors discuss the impact of the BDNF SNP on learning and memory while providing arguments for the relevance of a vertically integrated approach to studying human genetic variants.

Figure 1

Schematic representation of pro and mature brain-derived neurotrophic factor (BDNF) signaling pathways. Pro-BDNF binds preferentially to p75 neurotrophin receptor, activating nuclear factor κB (NF-κB) and c-Jun N-terminal kinase (JNK), leading to apoptosis and dendritic pruning. Mature BDNF binds specifically to tropomyosin-related kinase B (TrkB) receptor, activating mitogen-activated protein kinase (MAPK), phospholipase C gamma (PLC-γ), and phosphatidylinositol-3-kinase (PI3-K), leading to neuronal survival differentiation and synaptic plasticity.

Figure 2

The “bottom-up” approach to behavioral genetics begins in biologically less complex, genetically uniform systems, minimizing variability and providing external validation to gene association studies in the human population.

Figure 3

Comparison of brain-derived neurotrophic factor (BDNF) Val66Met in humans and mice.