Vitamin A Deficiency Impairs Spatial Learning and Memory: The Mechanism of Abnormal CBP-Dependent Histone Acetylation Regulated by Retinoic Acid Receptor Alpha
Vitamin A Deficiency Impairs Spatial Learning and Memory: The Mechanism of Abnormal CBP-Dependent Histone Acetylation Regulated by Retinoic Acid Receptor Alpha
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DOI：
10.1007/s12035-014-8741-6
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发表时间：
2015-04-01
影响因子：
5.1
通讯作者：
Li, Tingyu
中科院分区：
文献类型：
--
作者：
Hou, Nali;Ren, Lan;Li, Tingyu
维生素A（VA）是一种必需的微量营养素。大量研究证实，VA缺乏（VAD）导致学习记忆功能下降。我们以前的研究表明，海马中的视黄酸核受体α（RAR α）在学习和记忆中起着至关重要的作用，但这一过程的确切机制尚不清楚。表观遗传修饰，特别是组蛋白乙酰化，参与神经系统发育，学习和记忆功能，以及神经退行性疾病的发病机制。组蛋白乙酰转移酶（HAT），如CREB结合蛋白（CBP），E1 A结合蛋白p300（p300）和p300/CBP相关因子（PCAF），是调节记忆功能的关键。本研究以RAR α和CBP为例，探讨RA信号通路与组蛋白乙酰化修饰的关系，揭示VAD诱导学习记忆障碍的表观遗传学机制。本研究检测了8周龄大鼠海马中RAR α、HAT、乙酰化组蛋白H3/H4和记忆相关基因（Zif 268、cFos、FosB）的表达，以及RAR α和CBP的相互作用。此外，在抑制或过表达RAR α的原代培养的神经元中进一步评估体内显示的变化。我们发现VAD大鼠组蛋白乙酰化水平显著降低。此外，这种损害学习和记忆的下调是由RAR α介导的CBP依赖性组蛋白乙酰化的失调诱导的。这项工作提供了坚实的理论基础和实验基础，确保足够的营养VA在怀孕期间和生命早期，以防止成年后的学习和记忆障碍的重要性。
Vitamin A (VA) is an essential micronutrient. Numerous studies have confirmed that VA deficiency (VAD) leads to a decline in learning and memory function. Our previous studies have demonstrated that retinoic acid nuclear receptor alpha (RAR alpha) in the hippocampus plays a crucial role in learning and memory, but the exact mechanism for this process is unclear. Epigenetic modifications, particularly histone acetylation, are involved in nervous system development, learning and memory function, and the pathogenesis of neurodegenerative diseases. Histone acetyltransferases (HATs), such as CREB-binding protein (CBP), E1A-binding protein p300 (p300), and p300/CBP-associated factor (PCAF), are critical for regulating memory function. The current study uses RAR alpha and CBP as examples to study the connections between the RA signaling pathway and histone acetylation modification and to reveal the epigenetic mechanism in VAD-induced learning and memory impairment. This study examined the expression of RAR alpha, HATs, acetylated histone H3/H4, and memory-related genes (Zif268, cFos, FosB), as well as the interaction of RAR alpha and CBP in the hippocampus of 8-week-old rats. Additionally, the changes shown in vivo were further assessed in primary cultured neurons with the inhibition or overexpression of RAR alpha. We found significantly lower levels of histone acetylation in the VAD rats. Furthermore, this downregulation, which impairs learning and memory, is induced by the dysregulation of CBP-dependent histone acetylation that is mediated by RAR alpha. This work provides a solid theoretical foundation and experimental basis for the importance of ensuring sufficient nutritional VA during pregnancy and early life to prevent impairments of learning and memory in adulthood.