Toward a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: a model of impaired dendritic mRNA trafficking

Abstract

Brain-derived neurotrophic factor (BDNF) represents promotesa key molecule for the survival and differentiation of specific populations of neurons in the central nervous system. BDNF also regulates plasticity-related processes underlying memory and learning. A common single nucleotide polymorphism (SNP) rs6265 has been identified on the coding sequence of human BDNF located at 11p13. The SNP rs6265 is a single base mutation with an adenine instead of a guanine at position 196 (G196A), resulting in the amino acid substitution Val66Met. This polymorphism only exists in humans and has been associated with a plethora of effects ranging from molecular, cellular and brain structural modifications in association with deficits in social and cognitive functions. To date, the literature on Val66Met polymorphism describes a complex and often conflicting pattern of effects. In this review, we attempt to provide a unifying model of the Val66Met effects. We discuss the clinical evidence of the association between Val66Met and memory deficits, as well as the molecular mechanisms involved including the reduced transport of BDNF mRNA to the dendrites as well as the reduced processing and secretion of BDNF protein through the regulated secretory pathway.

Keywords: BDNF; dendritic mRNA trafficking; hippocampus atrophy; memory deficits; neurotrophins; post-traumatic stress disorder; regulated protein secretion.

Figure 1

Interaction between translin and human BDNF mRNA is hampered by the mutation G196A. (A) Translin amino acids His-90, Arg-21, Glu-89 form three hydrogen bonds with G196 (normal human BDNF) but only one with A196 (mutated BDNF, in B). (C) The nucleotide: amino acid selectivity for each of the four binding sites on translin. (D) Three-dimensional modeling of translin dimer binding to human BDNF mRNA.

Figure 2

Model of the biological effects of Val and Met BDNF alleles in the hippocampus. (A) In Val/Val neurons, the four most abundant brain BDNF transcripts, encoding exon 1, 2, 4, or 6, are differentially localized in dendrites, forming a gradient with exon 1 being restricted to the soma and exons 2, 4, and 6 in dendrites at increasing distances according to the gradient 4<2<6. Exons 1 and 4 can affect only the morphology of proximal dendrites while exon 2 and 6 are able to shape the distal dendrites. (B) In Met/Met neurons, transport of BDNF mRNA in distal dendritic districts is impaired and all BDNF mRNA isoforms accumulate in the cell soma. Met BDNF protein increases in the soma, also due to poor secretion. It is unclear if axonal transport and secretion can be affected by the Met mutation. (C) BDNF released from DG granule cells is shown in red, while BDNF released from CA3 neurons is shown in blue. (1.BDNF) Secretion of Met BDNF from the soma of DG granule cells is altered and provides insufficient local trophic support for survival and differentiation of DG subgranular neural stem cells. (2.BDNF) Release of Met BDNF from dendrites of DG neurons is affected and cannot provide sufficient autocrine support to dendrites which show reduced arborization. (3.BDNF) Local production and release of Met BDNF from apical dendrites of CA3 neurons is reduced and cannot provide the target-derived trophic support to promote innervation of CA3 from newly formed mossy fibers and autocrine support to CA3 dendrites. (4.BDNF) It is unknown if anterogradely transported Met BDNF in mossy fibers can support dendrites from CA3 neurons and if anterograde transport of BDNF is affected by the Met mutation.