Upregulation of NMDARI mRNA induced by MK-801 is associated with massive death of axotomized motor neurones in adult rats.
Upregulation of NMDARI mRNA induced by MK-801 is associated with massive death of axotomized motor neurones in adult rats.
复制标题
MK-801 诱导的 NMDARI mRNA 上调与成年大鼠轴突运动神经元的大量死亡有关。
DOI：
10.1006/nbdi.1994.0015
复制
发表时间：
1994
影响因子：
6.1
通讯作者：
Snider,WD
中科院分区：
文献类型：
--
作者：
Sanner,C;Elliott,JL;Snider,WD
由于缺乏成年动物运动神经元变性模型，人类运动神经元疾病的发病机制研究一直受到影响。正常情况下，在成年啮齿动物中，运动神经元轴突的横断只会导致适度的神经元死亡。我们推测，轴突切断诱导的运动神经元死亡可能通过调节谷氨酸能传递而增强。通过切断成年大鼠的面神经，然后在损伤后4周或8周存活期的第一周应用MK-801，我们在8周时诱导了67%的运动神经元丢失，而对照组的运动神经元丢失了19%。MK-801治疗后运动神经元丢失增加的一个可能解释是，短暂阻断NMDA受体可能上调NMDA受体成分的合成。为了验证这一观点，我们采用定量原位杂交的方法来确定NMDAR1mRNA对轴突切断和轴突切断+MK-801治疗的反应。对NMDAR1银粒在每个运动神经元胞体所占面积的百分比进行量化，表明单独切断轴突并不能引起NMDAR1mRNA的改变。然而，与对照组或单纯接受轴突切断的动物相比，切断轴突和MK-801联合治疗后，NMDAR1的mRNA表达显著上调。我们的结果表明，切断轴突后成年动物的运动神经元死亡可以增加，这与NMDA受体mRNA的上调有关。因此，谷氨酸受体信号的异常可能导致体内亚急性运动神经元的死亡。这些结果表明，MK-801短暂处理是一种方便的方法，可以提高成年动物轴突切断后运动神经元的死亡程度。
Studies on the pathogenesis of human motor neurone disease have suffered from the absence of models of motor neurone degeneration in adult animals. Normally in adult rodents, transection of motor neurone axons results in only a modest degree of neuronal death. We reasoned that axotomy-induced motor neurone death might be enhanced by modulating glutamatergic transmission. By axotomizing the facial nerve in adult rats and then administering MK-801 for the first week of a 4-week or 8-week post-lesion survival period, we induced a 67% motor neurone loss by 8 weeks as compared with a 19% loss in controls. A possible explanation for the increased motor neurone loss after MK-801 treatment is that transient blockade of NMDA receptors may upregulate synthesis of NMDA receptor components. In order to test this idea, we employed quantitativein situhybridization to determine the response of NMDAR1 mRNA to axotomy and axotomy + MK-801 treatment. Quantification of the percentage of area occupied by NMDAR1 silver grains per motor neurone somata indicated that axotomy alone did not provoke a change in NMDAR1 mRNA. However, axotomy and MK-801 combined treatment resulted in a highly significant upregulation of NMDAR1 mRNA when compared with controls or animals treated solely with axotomy.Our results suggest that motor neurone death in adult animals can be enhanced after axotomy in association with the upregulation of NMDA receptor mRNA. Thus, abnormalities in glutamate receptor signalling may lead to subacute motor neurone deathin vivo. Furthermore these results indicate that transient treatment with MK-801 is a convenient method for enhancing the degree of motor neurone death after axotomy in adult animals.