Maternal One-carbon Metabolism during the Periconceptional Period and Human Foetal Brain Growth: A Systematic Review

The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (> 17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538–1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (< 7 nmol/L) associated with a reduced foetal brain volume. Preconceptional folic acid supplement use and specific dietary patterns (associated with increased B vitamins and low homocysteine) increased foetal head size. Although early pregnancy maternal folate appears to be the most independent predictor of foetal brain growth, there is insufficient data to confirm the link between maternal folate and offspring risks for neurodevelopmental diseases.

Single-Input Multi-Output U-Net for Automated 2D Foetal Brain Segmentation of MR Images

In this work, we develop the Single-Input Multi-Output U-Net (SIMOU-Net), a hybrid network for foetal brain segmentation inspired by the original U-Net fused with the holistically nested edge detection (HED) network. The SIMOU-Net is similar to the original U-Net but it has a deeper architecture and takes account of the features extracted from each side output. It acts similar to an ensemble neural network, however, instead of averaging the outputs from several independently trained models, which is computationally expensive, our approach combines outputs from a single network to reduce the variance of predications and generalization errors. Experimental results using 200 normal foetal brains consisting of over 11,500 2D images produced Dice and Jaccard coefficients of 94.2 ± 5.9% and 88.7 ± 6.9%, respectively. We further tested the proposed network on 54 abnormal cases (over 3500 images) and achieved Dice and Jaccard coefficients of 91.2 ± 6.8% and 85.7 ± 6.6%, respectively.

LRFN5 locus structure is influenced by the individual’s sex and associated with autism

BackgroundLRFN5 is a brain-specific gene needed for synaptic development and plasticity. It is the only gene in a large 5.4 Mb topologically associating domain (TAD) on chromosome 14, which we term the LRFN5 locus. This locus is highly conserved, but has extensive copy number variation. MethodsLocus structure was studied by chromatin immunoprecipitation (chIP-onchip) in fibroblasts from individuals with autism and controls, supplemented with a capture-HiC determination of TAD structures in a family trio. LRFN5 expression was studied in foetal brain cell cultures. In addition, locus interaction was studied in four large and independent cohorts by measuring deviations from Hardy-Weinberg equilibrium of a common deletion polymorphism. ResultsWe found that locus structural changes are associated with developmental delay (DD) and autism spectrum disorders (ASD). In a large family, ASD in males segregated with a chromosome 14 haplotype carrying a 172 kb deletion upstream of LRFN5 . In a fibroblast capture-HiC study on an ASD-patient-parent trio, the ASDsusceptible haplotype (in the mother and her autistic son) had a TAD pattern different from both the father and a female control. When the trimethylated histone-3-lysine-9 chromatin (H3K9me3) profiles in fibroblasts from control males (n=6) and females (n=7) were compared, a male-female difference was observed around the LRFN5 gene itself (p<0.01). Intriguingly, in three cohorts of individuals with DD (n=8757), the number of heterozygotes of a common deletion polymorphism upstream of LRFN5 was 20-26% lower than expected from Hardy-Weinberg equilibrium. This indicates early allelic interaction, and the genomic conversions from heterozygosity to wildtype or deletion homozygosity were of equal magnitudes. In a control group of medical students (n=1416), such conversions were three times more common than in the DD-patient cohorts (p=0.00001). Hypothetically, such allelic interaction is needed to establish monoallelic expression, which we found in foetal brain cell cultures. LimitationsThe male-female difference in H3K9me3 profiles was based on fibroblast data from a small number of individuals, and the monoallelic expression data on a single experiment. ConclusionsTaken together, allelic interaction, monoallelic expression and sexdependent differences make the LRFN5 locus attractive for exploring the genetic basis of synaptic memory and high-functioning male autism.

Decreased content of ascorbic acid (vitamin C) in the brain of knockout mouse models of Na+,K+-ATPase-related neurologic disorders

Na+,K+-ATPase is a crucial protein responsible for maintaining the electrochemical gradients across the cell membrane. The Na+,K+-ATPase is comprised of catalytic α, β, and γ subunits. In adult brains, the α3 subunit, encoded by ATP1A3, is predominantly expressed in neurons, whereas the α2 subunit, encoded by ATP1A2, is expressed in glial cells. In foetal brains, the α2 is expressed in neurons as well. Mutations in α subunits cause a variety of neurologic disorders. Notably, the onset of symptoms in ATP1A2- and ATP1A3-related neurologic disorders is usually triggered by physiological or psychological stressors. To gain insight into the distinct roles of the α2 and α3 subunits in the developing foetal brain, whose developmental dysfunction may be a predisposing factor of neurologic disorders, we compared the phenotypes of mouse foetuses with double homozygous knockout of Atp1a2 and Atp1a3 (α2α3-dKO) to those with single knockout. The brain haemorrhage phenotype of α2α3-dKO was similar to that of homozygous knockout of the gene encoding ascorbic acid (ASC or vitamin C) transporter, SVCT2. The α2α3-dKO brain showed significantly decreased level of ASC compared with the wild-type (WT) and single knockout. We found that the ASC content in the basal ganglia and cerebellum was significantly lower in the adult Atp1a3 heterozygous knockout mouse (α3-HT) than in the WT. Interestingly, we observed a significant decrease in the ASC level in the basal ganglia and cerebellum of α3-HT in the peripartum period, during which mice are under physiological stress. These observations indicate that the α2 and α3 subunits independently contribute to the ASC level in the foetal brain and that the α3 subunit contributes to ASC transport in the adult basal ganglia and cerebellum. We propose that decreases in ASC levels may affect neural network development and are linked to the pathophysiology of ATP1A2- and ATP1A3-related neurologic disorders.

Effects of challenge dose and inoculation route of the virulent Neospora caninum Nc-Spain7 isolate in pregnant cattle at mid-gestation

Parameters such as pathogen dose and inoculation route are paramount in animal models when studying disease pathogenesis. Here, clinical findings, including foetal mortality, parasite transmission rates and lesion severity, and immune responses were evaluated in Asturiana pregnant heifers at day 110 of gestation challenged with a virulent (Nc-Spain7) Neospora caninum isolate. Four different doses of parasite tachyzoites were inoculated intravenously (IV1, 107 parasites, n = 6; IV2, 105, n = 6; IV3, 103, n = 6; and IV4, 102, n = 5), and the subcutaneous (SC) inoculation route was also assessed for the dose of 105 tachyzoites (SC, n = 6). In addition, a control group (n = 4 pregnant heifers) was evaluated. Foetal death was observed in all infected groups from 25 to 62 days post-infection, varying with the dose (IV1:4/6, IV2:3/6; IV4:2/5, IV3:1/6), and was three times less frequently associated with the SC route than IV inoculation (1/6 vs. 3/6). A dose-dependent effect for parasite loads in placental and foetal brain tissues was also detected. After SC challenge, a reduced number of tachyzoites were able to reach foetal brain tissues, and no lesions were observed. In calves, specific IgG responses in precolostral sera were mainly associated with high-dose groups (IV1 [100.0%] and IV2 [66.7%]), and cerebral parasite DNA detection was scarce (3/18). In dams, IFN-γ production and the dynamics of anti-N. caninum IgG antibodies varied with the dose, and the cell-mediated immune response was also found to be route-dependent. Our results confirm the influence of parasite dose and inoculation route on the outcome and dynamics of bovine neosporosis at mid-gestation.