MTHFR DEFICIENCY OR REDUCED INTAKE OF FOLATE OR CHOLINE IN PREGNANT MICE RESULTS IN IMPAIRED SHORT-TERM MEMORY AND INCREASED APOPTOSIS IN THE HIPPOCAMPUS OF WILD-TYPE OFFSPRING
MTHFR DEFICIENCY OR REDUCED INTAKE OF FOLATE OR CHOLINE IN PREGNANT MICE RESULTS IN IMPAIRED SHORT-TERM MEMORY AND INCREASED APOPTOSIS IN THE HIPPOCAMPUS OF WILD-TYPE OFFSPRING
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DOI：
10.1016/j.neuroscience.2015.04.067
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发表时间：
2015-08-06
期刊：
影响因子：
3.3
通讯作者：
Rozen, R.
中科院分区：
文献类型：
--
作者：
Jadavji, N. M.;Deng, L.;Rozen, R.
一碳代谢的遗传或营养障碍，伴随高同型半胱氨酸血症，可导致复杂的疾病，包括妊娠并发症和神经精神疾病。在早期的工作中，我们发现，完全缺乏亚甲基四氢叶酸还原酶（MTHFR）的小鼠，叶酸和同型半胱氨酸代谢的关键酶，有认知障碍，胆碱代谢紊乱。母亲对叶酸和胆碱的需求在怀孕期间增加，这些营养素的缺乏会导致几种负面结果，包括吸收增加和发育延迟。本研究的目的是调查母亲MTHFR遗传缺陷或母亲在怀孕期间叶酸或胆碱营养缺乏对3周龄MTHFR（+/+）后代的行为和神经生物学影响。将Mthfr（+/+）和Mthfr（+/-）雌性动物置于对照饲料（CD）中;将Mthfr（+/+）雌性动物置于整个妊娠期和哺乳期的叶酸缺乏饲料（FD）或胆碱缺乏饲料（ChDD）中，直至其后代3周龄。在后代中评估短期记忆，并评估海马组织的形态学变化、凋亡、增殖和胆碱代谢。母亲MTHFR缺乏导致后代短期记忆障碍。与野生型母鼠相比，这些母鼠的血浆同型半胱氨酸水平升高。子代血浆同型半胱氨酸无差异。在Mthfr（+/-）母亲的后代海马中观察到细胞凋亡和增殖增加。在母体FD和ChDD研究中，后代也表现出短期记忆障碍，海马细胞凋亡增加;在ChDD后代中观察到神经发生增加。胆碱乙酰转移酶蛋白在两个饮食组的后代海马中增加，甜菜碱在FD后代海马中减少。我们的研究结果揭示了MTHFR缺乏或饮食缺乏关键甲基供体的母鼠后代的短期记忆缺陷。我们认为，母亲在怀孕期间的一碳代谢的缺陷，可以通过细胞凋亡或改变胆碱代谢的后代海马功能障碍。(C)2015年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Genetic or nutritional disturbances in one-carbon metabolism, with associated hyperhomocysteinemia, can result in complex disorders including pregnancy complications and neuropsychiatric diseases. In earlier work, we showed that mice with a complete deficiency of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate and homocysteine metabolism, had cognitive impairment with disturbances in choline metabolism. Maternal demands for folate and choline are increased during pregnancy and deficiencies of these nutrients result in several negative outcomes including increased resorption and delayed development. The goal of this study was to investigate the behavioral and neurobiological impact of a maternal genetic deficiency in MTHFR or maternal nutritional deficiency of folate or choline during pregnancy on 3-week-old Mthfr(+/+) offspring. Mthfr(+/+) and Mthfr(+/-) females were placed on control diets (CD); and Mthfr(+/+) females were placed on folate-deficient diets (FD) or choline-deficient diets (ChDD) throughout pregnancy and lactation until their offspring were 3 weeks of age. Shortterm memory was assessed in offspring, and hippocampal tissue was evaluated for morphological changes, apoptosis, proliferation and choline metabolism. Maternal MTHFR deficiency resulted in short-term memory impairment in offspring. These dams had elevated levels of plasma homocysteine when compared with wild-type dams. There were no differences in plasma homocysteine in offspring. Increased apoptosis and proliferation was observed in the hippocampus of offspring from Mthfr(+/-) mothers. In the maternal FD and ChDD study, offspring also showed short-term memory impairment with increased apoptosis in the hippocampus; increased neurogenesis was observed in ChDD offspring. Choline acetyltransferase protein was increased in the offspring hippocampus of both dietary groups and betaine was decreased in the hippocampus of FD offspring. Our results reveal short-term memory deficits in the offspring of dams with MTHFR deficiency or dietary deficiencies of critical methyl donors. We suggest that deficiencies in maternal one-carbon metabolism during pregnancy can contribute to hippocampal dysfunction in offspring through apoptosis or altered choline metabolism. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.