PDF(Pubmed)
Abstract：
Impairment of one-carbon metabolism during pregnancy, either due to nutritional deficiencies in B9 or B12 vitamins or caused by specific genetic defects, is often associated with neurological defects, including cognitive dysfunction that persists even after vitamin supplementation. Animal nutritional models do not allow for conclusions regarding the specific brain mechanisms that may be modulated by systemic compensations. Using the Cre-lox system associated to the neuronal promoter Thy1.2, a knock-out model for the methionine synthase specifically in the brain was generated. Our results on the neurobehavioral development of offspring show that the absence of methionine synthase did not lead to growth retardation, despite an effective reduction of both its expression and the methylation status in brain tissues. Behaviors were differently affected according to their functional outcome. Only temporary retardations were recorded in the acquisition of vegetative functions during the suckling period, compared to a dramatic reduction in cognitive performance after weaning. Investigation of the glutamatergic synapses in cognitive areas showed a reduction of AMPA receptors phosphorylation and clustering, indicating an epigenomic effect of the neuronal deficiency of methionine synthase on the reduction of glutamatergic synapses excitability. Altogether, our data indicate that cognitive impairment associated with methionine synthase deficiency may not only result from neurodevelopmental abnormalities, but may also be the consequence of alterations in functional plasticity of the brain.
摘要：
怀孕期间一碳代谢受损，由于B9或B12维生素的营养缺乏或由特定的遗传缺陷引起，通常与神经系统缺陷有关，包括即使补充维生素后仍持续存在的认知功能障碍。动物营养模型不允许得出关于可以通过全身补偿调节的特定脑机制的结论。使用与神经元启动子Thy1.2相关的Cre-lox系统,产生了特异性在脑中的甲硫氨酸合酶的敲除模型。我们对后代神经行为发育的研究结果表明，蛋氨酸合成酶的缺乏不会导致生长迟缓，尽管有效降低了其在脑组织中的表达和甲基化状态。行为根据其功能结果而受到不同的影响。在哺乳期间，在获得营养功能时只记录了暂时的延迟，与断奶后认知能力显著下降相比。对认知区域谷氨酸能突触的研究表明，AMPA受体磷酸化和聚集减少，表明蛋氨酸合酶的神经元缺乏对谷氨酸能突触兴奋性降低的表观基因组效应。总之,我们的数据表明，与蛋氨酸合成酶缺乏相关的认知障碍可能不仅是神经发育异常的结果，但也可能是大脑功能可塑性改变的结果。
