Dual effects of increased glycogen synthase kinase-3β activity on adult neurogenesis
Dual effects of increased glycogen synthase kinase-3β activity on adult neurogenesis
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DOI：
10.1093/hmg/dds533
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发表时间：
2013-04-01
影响因子：
3.5
通讯作者：
Hernandez, Felix
中科院分区：
文献类型：
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作者：
Fuster-Matanzo, Almudena;Llorens-Martin, Maria;Hernandez, Felix
成体神经发生，即成体新神经元的产生，是由多种激酶和磷酸酶控制的过程，其中GSK3 β发挥重要作用。这种蛋白质在中枢神经系统中尤其丰富，其活动失调被认为在阿尔茨海默病等慢性疾病中起着关键作用。在此之前，我们报道了体内过表达GSK3 β （Tet/GSK3 β小鼠）导致成年神经发生改变，导致神经源性生态位耗损。在这里，我们进一步表征了这些改变，发现双皮质素标记关闭的延迟，未成熟前体的存活率和死亡率的变化以及成熟神经元总数的减少。此外，我们强调了炎症环境的重要性，确定了eotaxin可能是对成人神经发生有害影响的调节剂。利用条件系统，我们还探讨了GSK3活性增加的这些负面影响在强力霉素处理后是否容易恢复。我们发现，在有症状的小鼠中，转基因关闭可以逆转小胶质细胞增生、异常eotaxin水平以及上述未成熟神经元的改变。出乎意料的是，Tet/GSK3 β小鼠的成熟神经元和亚颗粒区神经元前体细胞数量的减少不能逆转。因此，尽管神经源性生态位耗损是一种终生持续的不可逆转的损伤，但成人神经发生的改变以及神经退行性疾病的改变可以部分恢复。
Adult neurogenesis, the generation of new neurons during the adulthood, is a process controlled by several kinases and phosphatases among which GSK3 beta exerts important functions. This protein is particularly abundant in the central nervous system, and its activity deregulation is believed to play a key role in chronic disorders such as Alzheimers disease. Previously, we reported that in vivo overexpression of GSK3 beta (Tet/GSK3 beta mice) causes alterations in adult neurogenesis, leading to a depletion of the neurogenic niches. Here, we have further characterized those alterations, finding a delay in the switching-off of doublecortin marker as well as changes in the survival and death rates of immature precursors and a decrease in the total number of mature neurons. Besides, we have highlighted the importance of the inflammatory environment, identifying eotaxin as a possible modulator of the detrimental effects on adult neurogenesis. Taking advantage of the conditional system, we have also explored whether these negative consequences of increasing GSK3 activity are susceptible to revert after doxycycline treatment. We show that transgene shutdown in symptomatic mice reverts microgliosis, abnormal eotaxin levels as well as the aforementioned alterations concerning immature neurons. Unexpectedly, the decrease in the number of mature neurons and neuronal precursor cells of the subgranular zone of Tet/GSK3 beta mice could not be reverted. Thus, alterations in adult neurogenesis and likely in neurodegenerative disorders can be restored in part, although neurogenic niche depletion represents a non-reversible damage persisting during lifetime with a remarkable impact in adult mature neurons.