Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: unraveling the genome to understand the mind.
Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: unraveling the genome to understand the mind.
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DOI：
10.1016/j.nbd.2010.01.008
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发表时间：
2010-07
影响因子：
6.1
通讯作者：
Eisch AJ
中科院分区：
文献类型：
--
作者：
Hsieh J;Eisch AJ
在中枢神经系统 (CNS) 成熟、分化的神经元中，表观遗传机制（包括 DNA 甲基化、组蛋白修饰和调节性非编码 RNA）在将经验和环境刺激编码为稳定的、对行为有意义的基因表达变化方面发挥着关键作用。例如，成熟海马神经元的表观遗传变化与学习和记忆以及包括抑郁症在内的各种神经精神疾病有关。随着最近（和有保证的）对成熟神经元表观遗传修饰的关注，人们很容易忘记表观遗传机制最初是因其在胚胎和出生后早期发育（包括神经发生）中促进分化和驱动细胞命运的能力而被描述的。鉴于成人大脑中持续神经发生的发现以及成人海马神经发生、海马功能和神经精神疾病之间的有趣联系，现在是时候对表观遗传学在成人海马神经发生中的作用的目前已知的情况进行回顾，以补充正在进行的关于表观遗传学在成熟神经元中的作用的讨论。成人海马神经发生的过程很复杂，神经干细胞（NSC）产生命运限制的祖细胞，并最终成熟的齿状回颗粒细胞。值得注意的是，神经发生发生在一个日益明确的“神经发生生态位”内，其中脉管系统、星形胶质细胞和神经元等成熟细胞元件释放可以动态调节神经发生的信号。在这里，我们回顾了成人神经发生的关键阶段和方面是由表观遗传机制驱动的证据。我们讨论神经干细胞及其后代中发生的对神经发生至关重要的内在变化。我们还讨论了生态位中细胞成分发生的外在变化如何导致神经发生的改变。最后，我们描述了表观遗传学对于理解神经精神疾病中海马神经发生之间关系的潜在相关性。我们建议，更深入地了解控制神经发生复杂过程（包括 NSC 的增殖和分化）的分子和遗传机制，将带来治疗神经精神疾病的新疗法。
In mature, differentiated neurons in the central nervous system (CNS), epigenetic mechanisms – including DNA methylation, histone modification, and regulatory noncoding RNAs – play critical roles in encoding experience and environmental stimuli into stable, behaviorally-meaningful changes in gene expression. For example, epigenetic changes in mature hippocampal neurons have been implicated in learning and memory and in a variety of neuropsychiatric disorders, including depression. With all the recent (and warranted) attention given to epigenetic modifications in mature neurons, it is easy to forget that epigenetic mechanisms were initially described for their ability to promote differentiation and drive cell fate in embryonic and early postnatal development, including neurogenesis. Given the discovery of ongoing neurogenesis in the adult brain and the intriguing links among adult hippocampal neurogenesis, hippocampal function, and neuropsychiatric disorders, it is timely to complement the ongoing discussions on the role of epigenetics in mature neurons with a review on what is currently known about the role of epigenetics in adult hippocampal neurogenesis. The process of adult hippocampal neurogenesis is complex, with neural stem cells (NSCs) giving rise to fate-restricted progenitors and eventually mature dentate gyrus granule cells. Notably, neurogenesis occurs within an increasingly well-defined “neurogenic niche”, where mature cellular elements like vasculature, astrocytes, and neurons release signals that can dynamically regulate neurogenesis. Here we review the evidence that key stages and aspects of adult neurogenesis are driven by epigenetic mechanisms. We discuss the intrinsic changes occurring within NSCs and their progeny that are critical for neurogenesis. We also discuss how extrinsic changes occurring in cellular components in the niche can result in altered neurogenesis. Finally we describe the potential relevance of epigenetics for understanding the relationship between hippocampal neurogenesis in neuropsychiatric disorders. We propose that a more thorough understanding of the molecular and genetic mechanisms that control the complex process of neurogenesis, including the proliferation and differentiation of NSCs, will lead to novel therapeutics for the treatment of neuropsychiatric disorders.
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