Brown D R
Department of Biochemistry, Cambridge University, Cambridge, CB2 1QW, United Kingdom.
Mol Cell Neurosci. 1999 May;13(5):379-89. doi: 10.1006/mcne.1999.0751.
Glutamate can be toxic to neurons although it is a neurotransmitter. Regulation of extracellular glutamate levels is essential for prevention of glutamate neurotoxicity. Astrocytes play a major role in clearance of glutamate released by neurons. A coculture system combining cerebellar cells and astrocytes was employed to investigate the astrocytic control of glutamate toxicity. Coculture of astrocytes with cerebellar neurons enhanced uptake of glutamate by astrocytes. Inhibition of glutamate uptake in a coculture system led to death of cerebellar cells. This toxicity could be inhibited by MK801. However, in the presence of the glutamate uptake inhibitor, there was no increase in glutamate in the cultures compared to when the neurons were not cocultured. This indicated that neurons become more susceptible to glutamate toxicity in the presence of astrocytes and thus become dependent on astrocytes for prevention of glutamate toxicity. Astrocytes treated with conditioned medium from cerebellar cells did not show an increase in glutamate uptake but medium from astrocytes exposed to neuron conditioned medium was toxic to cerebellar cells. This toxicity was due to glutamate present in the medium. This suggests that a soluble factor released by neurons signals to astrocytes that neurons are present and stimulates a signal back to neurons which causes an increased sensitivity to glutamate toxicity.
尽管谷氨酸是一种神经递质，但它对神经元可能有毒性。调节细胞外谷氨酸水平对于预防谷氨酸神经毒性至关重要。星形胶质细胞在清除神经元释放的谷氨酸方面起主要作用。采用小脑细胞和星形胶质细胞共培养系统来研究星形胶质细胞对谷氨酸毒性的控制。星形胶质细胞与小脑神经元共培养可增强星形胶质细胞对谷氨酸的摄取。在共培养系统中抑制谷氨酸摄取会导致小脑细胞死亡。这种毒性可被MK801抑制。然而，在存在谷氨酸摄取抑制剂的情况下，与未进行共培养的神经元相比，培养物中的谷氨酸并没有增加。这表明在有星形胶质细胞存在的情况下，神经元对谷氨酸毒性更敏感，因此在预防谷氨酸毒性方面变得依赖于星形胶质细胞。用小脑细胞的条件培养基处理的星形胶质细胞没有显示出谷氨酸摄取增加，但暴露于神经元条件培养基的星形胶质细胞的培养基对小脑细胞有毒性。这种毒性是由于培养基中存在的谷氨酸。这表明神经元释放的一种可溶性因子向星形胶质细胞发出神经元存在的信号，并刺激向神经元反馈的信号，从而导致对谷氨酸毒性的敏感性增加。
