Metabolomic and transcriptomic signatures of prenatal excessive methionine support nature rather than nurture in schizophrenia pathogenesis

Siwei Chen,Angele De Silva,Wedad Alhassen,Ryan Yoshimura,Pierre Baldi,Geoffrey W. Abbott,Amal Alachkar

doi:10.1038/s42003-020-01124-8

Siwei Chen, Angele De Silva + Show 5 more

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https://doi.org/10.1038/s42003-020-01124-8

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Journal: Communications Biology	Publication Date: Jul 30, 2020
Citations: 16	License type: open-access

Affiliation: University of California, Irvine

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 therapeutic targets for schizophrenia.

Highlights

The imbalance of prenatal micronutrients may perturb one-carbon (C1) metabolism and increase the risk for neuropsychiatric disorders
C1 metabolism impairments increase the risk for the development of neuropsychiatric deficit such as cognitive deficits, schizophrenia and autism spectrum disorders (ASD), and produces in animals permanent phenotypic changes that resemble those in the major neuropsychiatric disorders[16,17,18,19,20,21,22]
Animals born to a MET female and reared by a SAL female (MET → SAL) displayed similar behavioral phenotypes to those born to- and raised by their MET biological mothers (MET → MET): the MET → SAL displayed increased locomotor activity (P < 0.01, one-way ANOVA followed by Tukey’s post test, Fig. 1e), decreased Prepulse inhibition (PPI) ratios in the sensorimotor gating behavior (P < 0.001, one-way ANOVA followed by multiple comparisons test, Fig. 1f), and decreased percentage of correct arm choice alternation in the spontaneous T-maze alternation assay (P < 0.001, one-way ANOVA followed by Tukey’s post test, Fig. 1g) compared to SAL-SAL

Summary

Introduction

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. We 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. The necessity for a finely tuned one-carbon (C1) metabolism activity during pregnancy is supported by the role of micronutrients such as methionine, choline, vitamin B12, betaine, and folate in brain development through involvement in methylation processes[1,2,3,4,5,6,7,8,9]. The aim of this study is to investigate the early changes in the brain metabolome and transcriptome linked to methionine overload during the third week of pregnancy in mice, and whether the behavioral phenotype induced by excessive prenatal methionine can be rescued by caregiving during early life stages. Maternal hyperhomocysteinemia (as a result of the disrupted methionine metabolism) during the third trimester of pregnancy has been be associated with a two-fold increase in the risk of schizophrenia in the adult offspring[22]

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