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.

中文翻译：

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产前一碳代谢失调程序精神分裂症样缺陷。

甲硫氨酸-叶酸循环依赖的一碳代谢与精神分裂症的病理生理学有关。由于精神分裂症是一种发育障碍，我们检查了妊娠期间单碳代谢的扰动对小鼠后代的影响。在妊娠的最后一周，给怀孕的小鼠服用相当于其每日摄入量两倍的蛋氨酸。他们的后代（MET 小鼠）表现出类似精神分裂症的社交缺陷、认知障碍和刻板印象升高，神经发生和突触可塑性降低，并且 CA1 神经元中局部兴奋性突触连接异常减少。在 MET 小鼠中，只有一个编码 Npas4 转录因子的基因的神经转录物表达发生了 > 两倍的改变（下调）；引人注目的是，类似的 Npas4 下调发生在人类精神分裂症患者的前额叶皮层中。最后，典型（氟哌啶醇）和非典型（氯氮平）抗精神病药在 MET 小鼠中的治疗作用模拟了人类精神分裂症患者的作用。我们的数据支持 MET 小鼠作为精神分裂症模型的有效性，并揭示了蛋氨酸代谢作为潜在的预防和/或治疗目标。