Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Impact of maternal blood hyposerotonemia on adult wild-type progeny

ABSTRACT: Numerous mood and behavior disorders have developmental origin resulting from genetic and environmental interactions. Maternal blood serotonin (5-HT) depletion alters embryonic brain development, but its long-term impact on progeny has never been investigated. Here we demonstrate that maternal blood hyposerotonemia (60% deficit) induced hyperlocomotion, self-care deficit and increased anxiety in adult WT male offspring. Concomitantly, norepinephrine (NE) level and dopamine (DA) turnover were significantly reduced in the mesencephalon and brainstem, whereas monoaminergic cell density was not affected. In the frontal cortex, maternal hyposerotonemia caused a significant reduction in DA, NE and 5-HT levels, accompanied by transcriptomic changes, notably in monoaminergic system signaling, synaptic function and plasticity, methylation processes and myelination. Myelination was also defective as revealed by a reduced thickness of the corpus callosum. Maternal hyposerotonemia is thus sufficient to affect the phenotype of adult WT progeny. Maternal peripheral 5-HT deficit during pregnancy could thus be considered as a risk factor for neurodevelopmental disorders in the offspring.

INSTRUMENT(S): NextSeq 2000

ORGANISM(S): Mus musculus

SUBMITTER: genomiqueENS IBENS

PROVIDER: E-MTAB-15335 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Maternal 5-HT1A-receptor (R) is required for the timely development of the hippocampus and the establishment of emotional behaviors in Swiss-Webster (SW) mice. A partial and/or complete loss of maternal 5-HT1AR results in delayed ventral dentate granule cell (v-DGC) development and subsequent anxiety-like phenotype in the wild-type offspring by a non-genetic, presumably epigenetic mechanism. Here we tested v-DGCs for genome-wide DNA methylation changes elicited by the receptor deficient maternal environment. We identified a set of hypomethylated regions in the offspring of receptor deficient mothers. A significant fraction of these maternal-differentially methylated regions (m-DMRs) mapped to strong CpG islands, sequences that are typically not methylated or if methylated, resistant to environmental-induced changes. Many m-DMRs mapped to exons and some were associated with expression changes. Their hypomethylation was due to an arrest in de novo methylation and, to a lesser extent, to demethylation during postnatal life indicating that the perturbation in methylation coincides with the developmental delay in DGC maturation in the offspring of receptor deficient mothers. Inhibiting methylation in differentiating neurons impaired their maturation further suggesting a link between de novo methylation and neuronal differentiation. These data suggest that methylation at specific exonic CpG-islands may contribute to the mechanism through which maternal 5-HT1AR modulates hippocampal development and consecutively the level of anxiety in the SW offspring. Reduced 5-HT1AR-binding has been reported in individuals, particularly in association with anxiety/depression, including peri/postpartum depression. Therefore, maternal receptor deficit may contribute, via a non-genetic mechanism, to the high prevalence and heritability of anxiety disorders in human. Examined 4 samples: 5HT1A wild type offspring with 5HT1A wild type/heterozygous mother or 5HT1A KO offspring with 5HT1A of heterozygous/knock out mother

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Impact of maternal blood hyposerotonemia on adult wild-type progeny

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