135 Brain-derived neurotrophic factor polymorphism modifies the effects of developmental ethanol exposure


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Abstract

Purpose of studyFetal Alcohol Spectrum Disorder (FASD) is caused by in utero exposure to ethanol (EtOH) and is a leading cause of cognitive deficits. Brain-derived neurotrophic factor (BDNF) plays an integral role in neuronal development and may counteract some of the effects of developmental EtOH exposure. The val66Met missense mutation within the coding region of BDNF gene decreases BDNF secretion. The purpose of this study was to determine if there was an interaction between developmental EtOH exposure and the val66met BDNF polymorphism.Methods usedTimed pregnant transgenic dams homozygous for either valine (BDNFval/val) or methionine (BDNFmet/met) in residue 68, homologous to residue 66 in humans, were exposed to increasing concentrations of vaporised EtOH from gestational day 12 to 19, and again with pups on postnatal days (P) 2 to 9. On P15, P50, and P90 mice were perfused transcardially with paraformaldehyde and brains were processed for immunohistochemistry, including sectioning at 50 µm, parasagitally. Hippocampal volumes were assessed in sections stained with the nuclear dye DAPI using unbiased methods. Adult neurogenesis was assessed at P90 with Doublecortin (DCX) staining and counted with unbiased stereology. Anxiety-like behaviour was assessed using an elevated zero maze at P80. Learning and memory was assessed at P90 using trace fear conditioning.Summary of resultsDuring P15, EtOH exposure reduced hippocampal volume in the dentate gyrus (DG) (p=0.029) and the CA1 region (p=0.027) of BDNFmet/met but not BDNFval/val male mice; similar effects were seen in BDNFmet/met female cohorts in DG (p=0.027) and CA1 (p=0.029). During P90, EtOH exposure reduced anxiety-like behaviour (p=0.021) and learning and memory (p=0.0033) in BDNFmet/met male mice. Ethanol exposure reduced adult neurogenesis only in the ventral hippocampus of BDNFval/val male mice (p=0.042).ConclusionsHere, we suggest a novel interaction between developmental EtOH exposure and BDNFmet/met. Specifically, BDNFmet/met increased the effects of EtOH on hippocampal morphology and hippocampal-dependent behaviours. These findings suggest that screening for this polymorphism may have some value in predicting FASD severity.

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