Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr^+/− genotype to the different domains of behavior. Preconception and prenatal supplementation with methyl donor rich diet to human subjects and mice reduced the risk for developing autism and autistic-like behavior, respectively. Here we tested the potential of choline supplementation to Mthfr-deficient mice at young-adulthood to reduce behavioral and neurochemical changes reminiscent of autism characteristics. We show that offspring of Mthfr^+/− mothers, whether wildtype or heterozygote, exhibit autistic-like behavior, altered brain p62 protein levels and LC3-II/LC3-I levels ratio, both, autophagy markers. Choline supplementation to adult offspring of Mthfr^+/− mothers for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. The results demonstrate that choline supplementation even at adulthood, not tested previously, to offspring of Mthfr-deficient mothers, attenuates the autistic-like phenotype. If this proof of concept is replicated it might promote translation of these results to treatment recommendation for children with ASDs bearing similar genetic/metabolic make-up.

自闭症患者中大量报道了一种碳代谢失衡和异常自噬。亚甲基四氢叶酸还原酶 (Mthfr) 基因的多态性，编码该途径中的关键酶，与自闭症谱系障碍 (ASD) 的风险增加有关。已经描述了类似自闭症的核心和相关行为，母体和后代 Mthfr 的贡献^+/-不同行为领域的基因型。对人类受试者和小鼠进行富含甲基供体的饮食的孕前和产前补充分别降低了患自闭症和自闭症样行为的风险。在这里，我们测试了在成年期向缺乏 Mthfr 的小鼠补充胆碱以减少使人联想到自闭症特征的行为和神经化学变化的潜力。我们表明 Mthfr ^+/-母亲的后代，无论是野生型还是杂合子，都表现出自噬样行为，改变脑 p62 蛋白水平和 LC3-II/LC3-I 水平比率，两者都是自噬标志物。Mthfr 成年后代的胆碱补充^+/-14天的母亲抵消了雄性和雌性与重复行为和焦虑相关的特征，并仅改善了雄性小鼠的社交行为。胆碱治疗还使雄性小鼠中测量的自噬标记的异常皮质水平正常化。结果表明，即使在成年期补充胆碱（之前未测试过），对缺乏 Mthfr 的母亲的后代也能减轻自闭症样表型。如果这个概念证明被复制，它可能会促进将这些结果转化为对具有相似遗传/代谢构成的 ASD 儿童的治疗建议。