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The mouse-equivalent of the human BDNF VAL66MET polymorphism increases dorsal hippocampal volume and does not interact with developmental ethanol exposure.

ABSTRACT: A relatively common polymorphism in the human brain-derived neurotrophic factor (BDNF) gene (Val66Met, which corresponds to Val68Met in mice) has been shown to modulate cognitive function and vulnerability to mental health disorders. This substitution impairs trafficking and activity-dependent release of BDNF. A number of studies with both humans and transgenic mice suggest that carriers of the Met allele have deficits in the structure and/or function of the hippocampal formation. Using a relatively new transgenic mouse model of this polymorphism, we recently demonstrated that it modulates the effects of developmental ethanol exposure in the hippocampus. Here, we further characterized the effect of this polymorphism on hippocampal morphology and its interaction with ethanol vapor exposure during the 2nd and 3rd trimester equivalents of human pregnancy. We found that BDNF^met/met mice have slightly larger hippocampal volumes than BDNF^val/val mice. Ethanol vapor exposure during the 2nd and 3rd trimester equivalents of human pregnancy increased hippocampal volume in a single hippocampal subregion, the CA1 stratum radiatum. Ethanol exposure did not interact with BDNF genotype to affect volume in any hippocampal subregion. These results suggest that the Val66Met polymorphism does not reduce hippocampal size (i.e., it rather increases it slightly) or increase susceptibility to prenatal ethanol exposure-induced structural hippocampal damage during adulthood.

SUBMITTER: Bird CW

PROVIDER: S-EPMC7292775 | biostudies-literature |

REPOSITORIES: biostudies-literature

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BDNF val66met affects hippocampal volume and emotion-related hippocampal memory activity.

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Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory.

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Brain-derived neurotrophic factor (BDNF) Val66Met and adulthood chronic stress interact to affect depressive symptoms.

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BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function.

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BDNF Val66Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields.

Project description:Childhood stress and genetic factors like the Val66MET polymorphism of the brain derived neurotrophic factor (BDNF) gene are associated with a higher risk for developing major depressive disorder (MDD) and might also influence hippocampal changes. The aim of this study was to determine which hippocampal dentate gyrus and cornu ammonis subfields are altered in MDD compared to healthy controls and which subfields are affected by the BDNF Val66Met polymorphism and child adversity. Adult patients with MDD and healthy matched controls underwent high-resolution magnetic resonance imaging. Automatic segmentation using the programme FreeSurfer was used to segment the hippocampal subfields dentate gyrus (DG/CA4), CA1 and CA2/3. The history of possible childhood adversity was assessed using the Childhood Trauma Questionnaire and the Val66Met BDNF SNP (rs6265) genotypes were obtained. Patients with MDD had significantly smaller CA4/DG and CA2/3 volumes compared to healthy controls. Furthermore, there was a significant interactive effect of BDNF allele and childhood adversity on CA2/3 and CA4/DG volumes. Met allele carriers without childhood adversity had larger and with childhood adversity smaller CA4/DG and CA2/3 volumes than Val-allele homozygotes. Our results highlight stress by gene interactions as relevant for hippocampal volume reductions, in particular for the subfield CA2/3 and dentate gyrus.

| S-EPMC6869047 | biostudies-literature

Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects.

Project description:Brain-derived neurotrophic factor (BDNF) has been implicated in the mechanism of age-related regional brain volumetric changes. Healthy volunteers with the valine to methionine polymorphism at codon 66 of the BDNF gene (val66met) exhibit decreased volume of a number of brain structures, including hippocampus, temporal and occipital lobar gray matter volumes, and a negative correlation between age and the volume of bilateral dorsolateral prefrontal cortices. We sought to characterize the relationship between age, BDNF and amygdala volumes among healthy volunteers. We measured amygdala volumes in 55 healthy, right-handed volunteers who underwent structural magnetic resonance imaging (MRI) and were also characterized demographically and genotyped with respect to BDNF. Using an ANCOVA model, we found that amygdala volumes were inversely correlated with age in BDNF val66met carriers but not in non-carriers. This is the first report of age-related BDNF val66met polymorphism effects on amygdala volume.

| S-EPMC2674019 | biostudies-literature

BDNF val66met Polymorphism Impairs Hippocampal Long-Term Depression by Down-Regulation of 5-HT3 Receptors.

Project description:Brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal plasticity and cognitive functions. BDNF val66met polymorphism, a human single-nucleotide polymorphism (SNP) in the pro-domain of BDNF gene, is associated with deficits in activity-dependent BDNF secretion and hippocampus-dependent memory. However, the underlying mechanism remains unclear. Here we show that in the BDNFMet/Met mouse line mimicking the human SNP, BDNF expression in the hippocampus was decreased. There was a reduction in the total number of cells in hippocampal CA1 region, while hippocampal expression of mRNAs for NR2a, 2b, GluR1, 2 and GABAARβ3 subunits were up-regulated. Although basal glutamatergic neurotransmission was unaltered, hippocampal long-term depression (LTD) induced by low-frequency stimulation was impaired, which was partially rescued by exogenous application of BDNF. Interestingly, 5-HT3a receptors were down-regulated in the hippocampus of BDNFMet/Met mice, whereas 5-HT2c receptors were up-regulated. Moreover, impaired LTD in BDNFMet/Met mice was reversed by 5-HT3aR agonist. Thus, these observations indicate that BDNF val66met polymorphism changes hippocampal synaptic plasticity via down-regulation of 5-HT3a receptors, which may underlie cognition dysfunction of Met allele carriers.

| S-EPMC5643500 | biostudies-literature

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