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Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits

Abstract

The methionine-folate cycle-dependent one-carbon metabolism is implicated in the pathophysiology of schizophrenia. Since schizophrenia is a developmental disorder, we examined the effects that perturbation of the one-carbon metabolism during gestation has on mice progeny. Pregnant mice were administered methionine equivalent to double their daily intake during the last week of gestation. Their progeny (MET mice) exhibited schizophrenia-like social deficits, cognitive impairments and elevated stereotypy, decreased neurogenesis and synaptic plasticity, and abnormally reduced local excitatory synaptic connections in CA1 neurons. Neural transcript expression of only one gene, encoding the Npas4 transcription factor, was >twofold altered (downregulated) in MET mice; strikingly, similar Npas4 downregulation occurred in the prefrontal cortex of human patients with schizophrenia. Finally, therapeutic actions of typical (haloperidol) and atypical (clozapine) antipsychotics in MET mice mimicked effects in human schizophrenia patients. Our data support the validity of MET mice as a model for schizophrenia, and uncover methionine metabolism as a potential preventive and/or therapeutic target.

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Acknowledgements

This work was supported by the National Institute of Health (DA024746), CART and Eric L and Lila D Nelson Chair in Neuropharmacology. AA is supported by the Institute of International Education IIE-SRF fellowship.

Author contributions

AA and OC conceived the project and wrote the manuscript. AA, OC and LW designed the experiments. AA, LW, RY, SML and ZW conducted the experiments, ARH carried out the genetic analyses, XX and GWA supervised the transcriptomic and electrophysiological studies and helped with the preparation of the manuscript.

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Correspondence to A Alachkar.

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Alachkar, A., Wang, L., Yoshimura, R. et al. Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits. Mol Psychiatry 23, 282–294 (2018). https://doi.org/10.1038/mp.2017.164

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