Vitamin A deficiency impairs postnatal cognitive function via inhibition of neuronal calcium excitability in hippocampus
Vitamin A deficiency impairs postnatal cognitive function via inhibition of neuronal calcium excitability in hippocampus
复制标题
维生素 A 缺乏通过抑制海马神经元钙兴奋性损害产后认知功能
DOI：
10.1111/j.1471-4159.2012.07697.x
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发表时间：
2012-06-01
影响因子：
4.7
通讯作者：
Li, Ting Yu
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Yu, Qin;Li, Ting Yu
j . Neurochem。（2012） 121, 932943。维生素A （VA）对出生后大脑发育至关重要，维生素A缺乏（VAD）可导致大鼠学习和空间记忆障碍。VA的大部分生物学功能是由视黄酸（RA）介导的。为了研究VA缺陷的机制，研究人员给母鼠喂食元素饮食，使其血液VA水平达到正常、缺乏或严重缺乏的水平。穿梭箱和Morris水迷宫测试分别显示青少年VAD大鼠的学习能力和空间记忆受损（p 3035）。与VA正常大鼠相比，VAD大鼠的电生理显示较弱的长期增强。nmda诱导的钙（Ca2+）兴奋性检查显示，VAD大鼠在出生后发育过程中海马切片的兴奋性降低。与VA正常大鼠相比，VAD大鼠在出生后发育后期NMDA受体NR1 mRNA和蛋白表达降低（p 1030），视黄酸受体（RARa） mRNA和蛋白表达也存在差异。此外，培养的初级海马神经元在全反式ra或9顺式ra反应中显示出神经元Ca2+兴奋性增加，同时RARa和NR1表达增加，与体内观察到的相似。我们还发现，在RARa特异性沉默后，钙的兴奋性减弱，NR1 mRNA和蛋白的表达降低。最后，我们发现RA信号并不直接通过转录调控影响NR1的表达。这些数据支持了一个新的观点，即持续的出生后VAD抑制RARa的表达，从而通过不直接的转录调节降低NR1的表达，然后抑制海马神经元Ca2+兴奋性，影响长期增强，最终导致青少年主动学习和空间记忆的缺陷。
J. Neurochem. (2012) 121, 932943. Abstract Vitamin A (VA) is important for postnatal brain development, and VA deficiency (VAD) can cause learning and spatial memory deficits in rats. Most of the biological functions of VA are mediated by retinoic acid (RA). To investigate the mechanisms underlying VA deficits, mother rats were fed elemental diets to achieve blood VA levels classified as normal, deficient or severely deficient. Shuttle box and Morris water maze tests revealed impairments in learning ability and spatial memory, respectively, in adolescent VAD rats (p 3035). Electrophysiology showed weaker long-term potentiation in VAD rats compared to VA normal rats. Examination of NMDA-induced calcium (Ca2+) excitability revealed decreased excitability in hippocampal slices from VAD rats during postnatal development. Relative to VA normal rats, VAD rats also had decreased NMDA receptor NR1 mRNA and protein expression in later stages of postnatal development (p 1030), as well as differences in retinoic acid receptor (RARa) mRNA and protein expression. Furthermore, primary hippocampal neurons in culture showed increased neuronal Ca2+ excitability in response to all-trans-RA or 9-cis-RA, coupled with increases in RARa and NR1 expression similar to those observed in vivo. We also found weaker calcium excitability and lower expression of NR1 mRNA and protein after specific silencing of RARa. Finally, we found that RA signals affected the expression of NR1 do not directly through transcriptional regulation. These data support the new idea that continuous postnatal VAD inhibits RARa expression, which decreases NR1 expression via no direct transcriptional regulation and then inhibits hippocampal neuronal Ca2+excitability which affects long-term potentiation, finally producing deficits in active learning and spatial memory in adolescence.