Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits

Mol Psychiatry. 2018 Feb;23(2):282-294. doi: 10.1038/mp.2017.164. Epub 2017 Aug 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / therapeutic use
  • Basic Helix-Loop-Helix Transcription Factors / drug effects
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • CA1 Region, Hippocampal / drug effects
  • Clozapine / therapeutic use
  • Developmental Disabilities / physiopathology
  • Disease Models, Animal
  • Female
  • Folic Acid / metabolism
  • Haloperidol / therapeutic use
  • Humans
  • Male
  • Methionine / metabolism*
  • Mice
  • Neurogenesis
  • Neuronal Plasticity
  • One-Carbon Group Transferases / metabolism
  • Prefrontal Cortex / embryology
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Schizophrenia / metabolism*
  • Stereotyped Behavior / drug effects
  • Tetrahydrofolates


  • Antipsychotic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Npas4 protein, mouse
  • Tetrahydrofolates
  • Folic Acid
  • Methionine
  • One-Carbon Group Transferases
  • Clozapine
  • Haloperidol