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.

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

“…Pregnant mice that mated with the same male mouse were subcutaneously administered with L-Methionine (MET) at a dose of 750 mg/kg (Sigma-Aldrich) or saline (SAL) twice a day for 7-8 consecutive days from gestational day 14 until delivery. We chose a methionine dose and treatment schedule that were used previously by other groups [65][66][67][68] , and then by our group 23,25 , which corresponded to the regimens previously administered to humans, and was reported to exacerbate the psychotic symptoms in schizophrenia patients [26][27][28][29]69,70 .…”

“…Male mice were tested from postnatal week 8 to week 12 with a battery of behavioral paradigms in the following order: locomotion, spontaneous T-maze alternation, and prepulse inhibition. The sequence of specific assays spaced by 3-6 days inter-assay interval was adapted from our report 23 .…”

“…Microarray experiments and analysis were performed as previously described 77 . Total RNA was extracted (Qiagen) from one brain hemisphere of the 24-h-old pups (the opposite hemisphere to that used for metabolomics' analysis) according to the manufacturer's protocol, (the results of Transcriptomic analysis of the brains from adult Sal and MET pups were published in our previous report 23 ). RNA was then reverse-transcribed into cDNA and analyzed by "whole-transcript transcriptomics" using the GeneAtlas microarray system (Affymetrix) and the manufacturer's protocols.…”

“…The spontaneous T-maze alternation assay was carried out as described previously 23 . Mice were placed in the start area of the T-maze (Accuscan Instruments, Inc.) and allowed 30 s of acclimation before the start of each trial.…”

“…We recently examined the effects that disruption of C1 metabolism during gestation have on mice progeny. Pregnant mice were administered methionine equivalent to twice their daily dietary intake in their final week of gestation at the time of brain development 23 . The resulting pups exhibited a constellation of behavioral, electrophysiological and transcriptomic changes consistent with schizophrenia.…”