Espey M G, Kustova Y, Sei Y, Basile A S
Laboratory of Neuroscience, National Institute of Digestive Disorders and Kidney, National Institutes of Health, Bethesda, Maryland 20892-0008, USA.
J Neurochem. 1998 Nov;71(5):2079-87. doi: 10.1046/j.1471-4159.1998.71052079.x.
Mice infected with the LP-BM5 leukemia retrovirus mixture develop a progressive immunodeficiency with associated behavioral, histological, and neurochemical alterations consistent with glutamatergic hyperactivation. To gain insight into the contribution of excitatory amino acids to the neurodegeneration observed in these mice, their concentrations were measured in the CSF and striatal microdialysates. Glutamate concentrations were significantly elevated in CSF but not plasma as early as 4 weeks postinoculation. Steady-state glutamate levels in striatal microdialysates were increased threefold and could be reduced 40% by application of L-alpha-aminoadipate, an inhibitor of microglial glutamate transport. Stimulation of infected mice with KCl/L-trans-2,4-pyrrolidine dicarboxylate further increased glutamate levels 170-270% above those evoked in control mice. Tetrodotoxin suppressed the depolarization-evoked increase in glutamate by 88% in control mice, but it had only negligible effects in 40% of infected mice. Analysis of glutamate transport and catabolism suggests that abnormal astrocytic function does not contribute to the increase in basal extracellular glutamate levels. These findings are the first direct evidence that infection with an immunodeficiency-inducing retrovirus leads to a chronic elevation of extracellular free glutamate levels in the brain, which contributes to the neurodegenerative and cognitive deficits observed in these mice.
感染LP - BM5白血病逆转录病毒混合物的小鼠会出现进行性免疫缺陷，并伴有行为、组织学和神经化学改变，这些改变与谷氨酸能过度激活一致。为了深入了解兴奋性氨基酸在这些小鼠中观察到的神经退行性变中的作用，在脑脊液和纹状体微透析液中测量了它们的浓度。早在接种后4周，脑脊液中的谷氨酸浓度就显著升高，但血浆中没有。纹状体微透析液中的稳态谷氨酸水平增加了两倍，应用小胶质细胞谷氨酸转运抑制剂L-α-氨基己二酸可使其降低40%。用氯化钾/L-反式-2,4-吡咯烷二羧酸刺激感染小鼠，可使谷氨酸水平比对照小鼠诱发的水平进一步升高170 - 270%。河豚毒素在对照小鼠中可将去极化诱发的谷氨酸增加抑制88%，但在40%的感染小鼠中其作用可忽略不计。对谷氨酸转运和分解代谢的分析表明，星形胶质细胞功能异常并非基础细胞外谷氨酸水平升高的原因。这些发现首次直接证明，感染免疫缺陷诱导型逆转录病毒会导致大脑中细胞外游离谷氨酸水平慢性升高，这导致了这些小鼠中观察到的神经退行性变和认知缺陷。
