Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
J Nutr. 2013 Jul;143(7):1028-35. doi: 10.3945/jn.113.174417. Epub 2013 May 22.
Impaired folate-mediated one-carbon metabolism (OCM) has emerged as a risk factor for several diseases associated with age-related cognitive decline, but the underlying mechanisms remain unknown and thus hinder the identification of subpopulations most vulnerable to OCM disruption. Here we investigated the role of serine hydroxymethyltransferase 1 (SHMT1), a folate-dependent enzyme regulating de novo thymidylate biosynthesis, in influencing neuronal and cognitive function in the adult mouse. We observed Shmt1 expression in the hippocampus, including the granule cell layer of the dentate gyrus (DG), and examined hippocampal neurogenesis and hippocampal-dependent fear conditioning in mice deficient for Shmt1. We used a 3 × 3 design in which adult male Shmt1(+/+), Shmt1(+/-), and Shmt1(-/-) mice were fed folic acid control (2 mg/kg), folic acid-deficient (0 mg/kg), or folic acid-supplemented (8 mg/kg) diets from weaning through the duration of the study. Proliferation within the DG was elevated by 70% in Shmt1(+/-) mice, yet the number of newborn mature neurons was reduced by 98% compared with that in Shmt1(+/+) mice. Concomitant with these alterations, Shmt1(+/-) mice showed a 45% reduction in mnemonic recall during trace fear conditioning. Dietary folate manipulations alone did not influence neural outcomes. Together, these data identify SHMT1 as one of the first enzymes within the OCM pathway to regulate neuronal and cognitive profiles and implicate impaired thymidylate biosynthesis in the etiology of folate-related neuropathogenesis.
一碳代谢（OCM）中叶酸介导的功能障碍已成为与年龄相关的认知能力下降相关的几种疾病的风险因素，但潜在机制尚不清楚，因此阻碍了识别最易受 OCM 破坏影响的亚群。在这里，我们研究了丝氨酸羟甲基转移酶 1（SHMT1）在调节从头胸苷酸生物合成中的作用，该酶是一种依赖叶酸的酶，在调节成年小鼠的神经元和认知功能中的作用。我们观察到 SHMT1 在海马中的表达，包括齿状回（DG）的颗粒细胞层，并研究了 SHMT1 缺陷型小鼠的海马神经发生和海马依赖性恐惧条件反射。我们使用 3×3 设计，其中成年雄性 Shmt1(+/+)、Shmt1(+/-)和 Shmt1(-/-) 小鼠从断奶开始到研究结束，用叶酸对照（2mg/kg）、叶酸缺乏（0mg/kg）或叶酸补充（8mg/kg）饮食喂养。Shmt1(+/-) 小鼠 DG 内的增殖增加了 70%，但与 Shmt1(+/+) 小鼠相比，新生成熟神经元的数量减少了 98%。伴随着这些改变，Shmt1(+/-) 小鼠在痕迹恐惧条件反射中记忆召回减少了 45%。单独的饮食叶酸处理不会影响神经结果。这些数据表明，SHMT1 是 OCM 途径中第一个调节神经元和认知特征的酶之一，并表明胸苷酸生物合成受损在叶酸相关神经发病机制中的作用。
