Steullet P, Neijt H C, Cuénod M, Do K Q
Center for Psychiatric Neurosciences, Department of Adult Psychiatry, University Medical Center, University of Lausanne, 1008 Prilly, Switzerland.
Neuroscience. 2006 Feb;137(3):807-19. doi: 10.1016/j.neuroscience.2005.10.014. Epub 2005 Dec 5.
Increasing evidence suggests that the metabolism of glutathione, an endogenous redox regulator, is abnormal in schizophrenia. Patients show a deficit in glutathione levels in the cerebrospinal fluid and prefrontal cortex and a reduction in gene expression of the glutathione synthesizing enzymes. We investigated whether such glutathione deficit altered synaptic transmission and plasticity in slices of rat hippocampus, with particular emphasis on NMDA receptor function. An approximately 40% decrease in brain glutathione levels was induced by s.c. administration of L-buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis. Such glutathione deficit did not affect the basal synaptic transmission, but produced several NMDA receptor-dependent and -independent effects. Glutathione deficit caused an increase in excitability of CA1 pyramidal cells. The paired-pulse facilitation was diminished in glutathione-depleted slices, in a manner that was independent of NMDA receptor activity. This suggests that lowering glutathione levels altered presynaptic mechanisms involved in neurotransmitter release. NMDA receptor-dependent long-term potentiation induced by high-frequency stimulation was impaired in glutathione-depleted slices. Pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials were significantly smaller in L-buthionine-(S,R)-sulfoximine-treated than in control slices. Hypofunction of NMDA receptors under glutathione deficit was explained at least in part by an excessive oxidation of the extracellular redox-sensitive sites of the NMDA receptors. These results indicate that a glutathione deficit, like that observed in schizophrenics, alters short- and long-term synaptic plasticity and affects NMDA receptor function. Thus, glutathione deficit could be one causal factor for the hypofunction of NMDA receptors in schizophrenia.
越来越多的证据表明，内源性氧化还原调节剂谷胱甘肽的代谢在精神分裂症中是异常的。患者脑脊液和前额叶皮质中的谷胱甘肽水平不足，且谷胱甘肽合成酶的基因表达降低。我们研究了这种谷胱甘肽缺乏是否会改变大鼠海马切片中的突触传递和可塑性，尤其着重于N-甲基-D-天冬氨酸（NMDA）受体功能。通过皮下注射谷胱甘肽合成抑制剂L-丁硫氨酸-（S，R）-亚砜亚胺，可使脑内谷胱甘肽水平降低约40%。这种谷胱甘肽缺乏并不影响基础突触传递，但产生了几种依赖和不依赖NMDA受体的效应。谷胱甘肽缺乏导致CA1锥体细胞兴奋性增加。在谷胱甘肽耗尽的切片中，双脉冲易化作用减弱，其方式与NMDA受体活性无关。这表明降低谷胱甘肽水平改变了参与神经递质释放的突触前机制。在谷胱甘肽耗尽的切片中，高频刺激诱导的依赖NMDA受体的长时程增强受损。在L-丁硫氨酸-（S，R）-亚砜亚胺处理的切片中，药理学分离的NMDA受体介导的场兴奋性突触后电位明显小于对照切片。谷胱甘肽缺乏时NMDA受体功能低下至少部分是由NMDA受体细胞外氧化还原敏感位点的过度氧化所解释的。这些结果表明，如在精神分裂症患者中观察到的那样，谷胱甘肽缺乏会改变短期和长期突触可塑性，并影响NMDA受体功能。因此，谷胱甘肽缺乏可能是精神分裂症中NMDA受体功能低下的一个因果因素。
