Foti Stacey Beth, Chou Athena, Moll Andrew D, Roskams A Jane
Department of Zoology, Life Sciences Institute and Brain Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Int J Dev Neurosci. 2013 Oct;31(6):434-47. doi: 10.1016/j.ijdevneu.2013.03.008. Epub 2013 Mar 27.
The mammalian central nervous system (CNS) undergoes significant expansion postnatally, producing astrocytes, oligodendrocytes and inhibitory neurons to modulate the activity of neural circuits. This is coincident in humans with the emergence of pediatric epilepsy, a condition commonly treated with valproate/valproic acid (VPA), a potent inhibitor of histone deacetylases (HDACs). The sequential activity of specific HDACs, however, may be essential for the differentiation of distinct subpopulations of neurons and glia. Here, we show that different subsets of CNS neural stem cells (NSCs) and progenitors switch expression of HDAC1 and HDAC2 as they commit to a neurogenic lineage in the subventricular zone (SVZ) and dentate gyrus (DG). The administration of VPA for only one week from P7-P14, combined with sequential injections of thymidine analogs reveals that VPA stimulates a significant and differential decrease in the production and differentiation of progeny of NSCs in the DG, rostral migratory stream (RMS), and olfactory bulb (OB). Cross-fostering VPA-treated mice revealed, however, that a postnatal failure to thrive induced by VPA treatment had a greater effect on DG neurogenesis than VPA action directly. By one month after VPA, OB interneuron genesis was significantly and differentially reduced in both periglomerular and granule neurons. Using neurosphere assays to test if VPA directly regulates NSC activity, we found that short term treatment with VPA in vivo reduced neurosphere numbers and size, a phenotype that was also obtained in neurospheres from control mice treated with VPA and an alternative HDAC inhibitor, Trichostatin A (TSA) at 0 and 3 days in vitro (DIV). Collectively, these data show that clinically used HDAC inhibitors like VPA and TSA can perturb postnatal neurogenesis; and their use should be carefully considered, especially in individuals whose brains are actively undergoing key postnatal time windows of development.
哺乳动物的中枢神经系统（CNS）在出生后会经历显著扩张，产生星形胶质细胞、少突胶质细胞和抑制性神经元，以调节神经回路的活动。这在人类中与小儿癫痫的出现同时发生，小儿癫痫通常用丙戊酸盐/丙戊酸（VPA）治疗，VPA是组蛋白脱乙酰酶（HDACs）的强效抑制剂。然而，特定HDACs的顺序活性可能对不同亚群的神经元和神经胶质细胞的分化至关重要。在这里，我们表明，中枢神经系统神经干细胞（NSCs）和祖细胞的不同亚群在进入脑室下区（SVZ）和齿状回（DG）的神经发生谱系时会切换HDAC1和HDAC2的表达。从P7到P14仅给予一周的VPA，并结合胸腺嘧啶类似物的顺序注射，结果显示VPA显著且差异性地减少了DG、嘴侧迁移流（RMS）和嗅球（OB）中NSCs子代的产生和分化。然而，对VPA处理的小鼠进行交叉寄养实验发现，VPA处理导致的出生后发育不良对DG神经发生的影响比VPA的直接作用更大。VPA处理一个月后，OB中间神经元在球周神经元和颗粒神经元中的生成均显著且差异性地减少。使用神经球分析来测试VPA是否直接调节NSC活性，我们发现体内短期使用VPA会减少神经球的数量和大小，在用VPA和另一种HDAC抑制剂曲古抑菌素A（TSA）在体外0天和3天（DIV）处理的对照小鼠的神经球中也获得了这种表型。总体而言，这些数据表明，临床上使用的HDAC抑制剂如VPA和TSA会干扰出生后的神经发生；其使用应谨慎考虑，尤其是在大脑正处于关键的出生后发育时间窗的个体中。
