Medina L, Figueredo-Cardenas G, Rothstein J D, Reiner A
Department of Anatomy and Neurobiology, University of Tennessee, Memphis 38163, USA.
Exp Neurol. 1996 Dec;142(2):287-95. doi: 10.1006/exnr.1996.0198.
Previous studies have suggested that defective high-affinity glutamate uptake, due mainly to a major loss of the astroglial-specific GLT-1 glutamate transporter, underlies the selective motoneuron degeneration observed in sporadic ALS (24, 28). If a defect in glutamate transport underlies the pathogenesis of sporadic ALS, the glutamate transporter subtype found to be lost in sporadic ALS should be present in abundance in the affected motor nuclei under normal conditions. To investigate this, we used immunohistochemical methods to analyze the localization of two subtypes of high-affinity glutamate transporters in the cranial motor nuclei of normal monkey brain stem: GLT-1, localized to astroglia; and EAAC1, localized to neurons. Our results indicated that all motor cell groups of monkey brain stem are rich in the GLT-1 glutamate transporter, which is localized to astroglial cells and processes that surround and envelop motoneuron cell bodies and dendrites. Image analysis indicated that the abundance of GLT-1 immunoreactive astroglial elements in ALS-vulnerable motor cell groups (i.e., the trigeminal, facial, and hypoglossal motor cell groups) is higher than in ALS-resistant motor cell groups (i.e., the oculomotor, trochlear, and abducens motor cell groups), and statistical analysis showed that this difference is significant. Our results also indicated that both ALS-vulnerable and ALS-resistant motor cell groups of monkey brain stem are relatively poor in EAAC1 immunoreactivity. Therefore, in the case of a loss in the GLT-1 glutamate transporter in sporadic ALS, glutamate may increase in the vicinity of motoneurons in all brain-stem motor cell groups, but especially in the ALS-vulnerable motor cell groups, which are normally richer in GLT-1. Increased extracellular glutamate could lead to excess entry of Ca2+ into motoneurons via glutamate-gated or voltage-activated Ca2+ channels and produce degeneration of those motoneurons unable to resist the insult. Since motoneurons in the ALS-resistant motor cell groups of the brain stem are enriched in the Ca2+ buffering protein parvalbumin, they should be better able to resist the damage than the majority of motoneurons in the ALS-vulnerable motor cell groups, which lack parvalbumin (20).
先前的研究表明，主要由于星形胶质细胞特异性谷氨酸转运体GLT-1大量缺失导致的高亲和力谷氨酸摄取缺陷，是散发性肌萎缩侧索硬化症（ALS）中观察到的选择性运动神经元变性的基础（24, 28）。如果谷氨酸转运缺陷是散发性ALS发病机制的基础，那么在散发性ALS中发现缺失的谷氨酸转运体亚型在正常情况下应大量存在于受影响的运动核中。为了研究这一点，我们使用免疫组织化学方法分析了正常猴脑干颅运动核中两种高亲和力谷氨酸转运体亚型的定位：GLT-1，定位于星形胶质细胞；以及EAAC1，定位于神经元。我们的结果表明，猴脑干的所有运动细胞群都富含GLT-1谷氨酸转运体，其定位于围绕并包裹运动神经元细胞体和树突的星形胶质细胞及其突起。图像分析表明，ALS易损运动细胞群（即三叉神经、面神经和舌下神经运动细胞群）中GLT-1免疫反应性星形胶质细胞成分的丰度高于ALS抗性运动细胞群（即动眼神经、滑车神经和展神经运动细胞群），统计分析表明这种差异具有显著性。我们的结果还表明，猴脑干的ALS易损和ALS抗性运动细胞群中EAAC1免疫反应性都相对较低。因此，在散发性ALS中GLT-1谷氨酸转运体缺失的情况下，所有脑干运动细胞群中运动神经元附近的谷氨酸可能会增加，但在通常富含GLT-1的ALS易损运动细胞群中尤其如此。细胞外谷氨酸增加可能导致Ca2+通过谷氨酸门控或电压激活的Ca2+通道过度进入运动神经元，并使那些无法抵抗损伤的运动神经元发生变性。由于脑干中ALS抗性运动细胞群中的运动神经元富含Ca2+缓冲蛋白小白蛋白，它们应该比缺乏小白蛋白的ALS易损运动细胞群中的大多数运动神经元更能抵抗损伤（20）。
