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Prenatal Stress-induced Depressive-like Behavior is Associated with Brain Metabotranscriptome Remodeling and is Reversed by Acetyl-carnitine

ABSTRACT: Intergenerational stress increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational stress transmission is a consequence of in-utero neurodevelopmental disruptions or early-life mother-infant interaction is largely unknown, due to the complexity, superposition, and inseparability between the prenatal and postnatal mechanisms. Here we show that prenatal stress, through exposing pregnant mice to predator scent, induces depressive-like behavior and social deficits. Cross-fostering experiments indicate divergent and convergent mechanisms of both in utero and early-life parenting environments and support a two-hit model of stress transmission. According to this model, prenatal stress (first-hit) primes brain metabolome and transcriptome (metabotranscriptome), and increases vulnerability to the second-hit in early life, triggered by poor caregiving by the traumatized mothers. Metabolomics, transcriptomic and bioinformatics analyses reveal mechanisms that involve stress- and hypoxia- response metabolic pathways in the brains of the newborn mice, likely through the production of the epigenetic modifiers 2-Hydroxyglutaric acid and succinic acid. These responses produce long-lasting alterations in mitochondrial-energy metabolism, and epigenetic processes pertaining to DNA and chromatin modifications. We demonstrate that an early pharmacological intervention – correction of the mitochondria metabolism, and epigenetic modifications with acetyl-L-carnitine (ALCAR) supplementation - produces long-lasting protection against the behavioral deficits associated with intergenerational transmission of traumatic stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE171275 | GEO | 2021/04/01

REPOSITORIES: GEO

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Metabolomic and Transcriptomic Signatures of Prenatal Excessive Methionine in Mice Support Nature Rather than Nurture in the Pathogenesis and Therapy of Schizophrenia

Project description:Abstract: The imbalance of prenatal micronutrients may perturb one-carbon (C1) metabolism and increase the risk for neuropsychiatric disorders. Prenatal excessive methionine (MET) produces in mice behavioral phenotypes reminiscent of human schizophrenia. Whether in-utero programming or early life caregiving mediate these effects is, however, unknown. Here, we show that the behavioral deficits of MET are independent of the early life mother-infant interaction. We also show that MET produces in early life profound changes in the brain C1 pathway components as well as glutamate transmission, mitochondrial function, and lipid metabolism. Bioinformatics analysis integrating metabolomics and transcriptomic data reveal dysregulations of glutamate transmission and lipid metabolism, and identify perturbed pathways of methylation and redox reactions. Our transcriptomics Linkage analysis of MET mice and schizophrenia subjects reveals master genes involved in inflammation and myelination. Finally, we identify potential metabolites as early biomarkers for neurodevelopmental defects and suggest new therapeutic targets for schizophrenia.

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