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.

Keywords: Brain derived neurotrophic factor; development; ethanol; fetal alcohol; hippocampal volume; hippocampus.

Figure 1.

The BDNF Val68Met polymorphism increases the total volume of the hippocampal formation but does not interact with developmental alcohol exposure. A) Representative parasagittal hippocampal section stained with neuronal marker illustrating the contours used to determine volumes (1. CA1 Stratum Oriens, 2. CA1 Stratum Radiatum, 3. CA1 Stratum Lacunosum Moleculare, 4. CA3 Stratum Oriens, 5. Stratum Radiatum/Lucidum, 6. Dentate Gyrus Molecular Layer). B) Effect of the polymorphism and alcohol exposure on total hippocampal volume. Black bars represent air-exposed animals; white bars represent ethanol-exposed animals. Genotype main effect p < 0.001; sex main effect p = 0.038. Hippocampal volumes in μm³ are presented for control male Val/Val (n=8 pups from 5 litters), ethanol male Val/Val (n=8 pups from 4 litters), control male Met/Met (n=8 pups from 4 litters), ethanol male Met/Met (n=8 pups from 4 litters), control female Val/Val (n=9 pups from 4 litters), ethanol female Val/Val (n=11 pups from 7 litters), control female Met/Met (n=8 pups from 4 litters), and ethanol female Met/Met (n=8 pups from 4 litters). For details on the results of statistical analyses, please see text and Supplementary Table 1. The red dotted line represents the volume of the air-exposed male Val/Val mice to illustrate differences between groups.

Figure 2.

The BDNF Val68Met polymorphism increases the volume of the CA1 hippocampal region but does not interact with developmental alcohol exposure. Black bars represent air-exposed animals; white bars represent ethanol-exposed animals. Shown are volumes for A) Entire CA1 region (genotype main effect p < 0.001; sex main effect p = 0.007, B) Stratum Oriens (genotype main effect p = 0.005; sex main effect p = 0.005), C) Stratum Radiatum (genotype main effect p <0.001; exposure main effect p = 0.005), and D) Stratum Lacunosum Moleculare (genotype main effect p = 0.032; sex main effect p = 0.004). Hippocampal volumes in μm³ are presented for control male Val/Val (n=8 pups from 5 litters), ethanol male Val/Val (n=8 pups from 4 litters), control male Met/Met (n=8 pups from 4 litters), ethanol male Met/Met (n=8 pups from 4 litters), control female Val/Val (n=9 pups from 4 litters), ethanol female Val/Val (n=11 pups from 7 litters), control female Met/Met (n=8 pups from 4 litters), and ethanol female Met/Met (n=8 pups from 4 litters). For details on the results of statistical analyses, please see text and Supplementary Table 1. The red dotted line represents the volume of the air-exposed male Val/Val mice to illustrate differences between groups.

Figure 3.

The BDNF Val68Met polymorphism increases the volume of the CA3 hippocampal region but does not interact with developmental alcohol exposure. Black bars represent air-exposed animals; white bars represent ethanol-exposed animals. Shown are volumes for A) Entire CA3 region (genotype main effect p = 0.005), B) Stratum Oriens (genotype main effect p = 0.002), and C) Stratum Radiatum/Lucidum (genotype main effect p = 0.016). Hippocampal volumes in μm³ are presented for control male Val/Val (n=8 pups from 5 litters), ethanol male Val/Val (n=8 pups from 4 litters), control male Met/Met (n=8 pups from 4 litters), ethanol male Met/Met (n=8 pups from 4 litters), control female Val/Val (n=9 pups from 4 litters), ethanol female Val/Val (n=11 pups from 7 litters), control female Met/Met (n=8 pups from 4 litters), and ethanol female Met/Met (n=8 pups from 4 litters). For details on the results of statistical analyses, please see text and Supplementary Table 1. The red dotted line represents the volume of the air-exposed male Val/Val mice to illustrate differences between groups.

Figure 4.

The BDNF Val68Met polymorphism increases the volume of the dentate gyrus molecular layer but does not interact with developmental alcohol exposure. Black bars represent air-exposed animals; white bars represent ethanol-exposed animals. Genotype main effect p < 0.001. Hippocampal volumes in μm³ are presented for control male Val/Val (n=8 pups from 5 litters), ethanol male Val/Val (n=8 pups from 4 litters), control male Met/Met (n=8 pups from 4 litters), ethanol male Met/Met (n=8 pups from 4 litters), control female Val/Val (n=9 pups from 4 litters), ethanol female Val/Val (n=11 pups from 7 litters), control female Met/Met (n=8 pups from 4 litters), ethanol female Met/Met (n=8 pups from 4 litters). For details on the results of statistical analyses, please see text and Supplementary Table 1. The red dotted line represents the volume of the air-exposed male Val/Val mice to illustrate differences between groups.