Tsai G, Passani L A, Slusher B S, Carter R, Baer L, Kleinman J E, Coyle J T
Laboratory of Molecular and Developmental Neuroscience, Harvard Medical School, Boston, USA.
Arch Gen Psychiatry. 1995 Oct;52(10):829-36. doi: 10.1001/archpsyc.1995.03950220039008.
Schizophrenia has been hypothesized to be caused by a hypofunction of glutamatergic neurons. Findings of reduced concentrations of glutamate in the cerebrospinal fluid of patients with schizophrenia and the ability of glutamate-receptor antagonists to cause psychotic symptoms lend support to this hypothesis. N-acetylaspartylglutamate (NAAG), a neuropeptide that is highly concentrated in glutamatergic neurons, antagonizes the effects of glutamate at N-methyl-D-aspartate receptors. Moreover, NAAG is cleaved to glutamate and N-acetylaspartate by a specific peptidase, N-acetyl-alpha-linked acidic dipeptidase (NAALADase). To test the glutamatergic hypothesis of schizophrenia, we studied the NAAG-related glutamatergic variables in postmortem brains from patients with schizophrenia, neuroleptic-treated controls, and normal individuals, with particular emphasis on the prefrontal cortex and hippocampus.
Different regions of frozen brain tissue from three different groups (patients with schizophrenia, neuroleptic-treated controls, and normal controls) were assayed to determine levels of NAAG, N-acetylaspartate, NAALADase, and several amino acids, including aspartate and glutamate.
Our study demonstrates alterations in brain levels of aspartate, glutamate, and NAAG and in NAALADase activity. Levels of NAAG were increased and NAALADase activity and glutamate levels were decreased in the schizophrenic brains. Notably, the changes in NAAG level and NAALADase activity in schizophrenic brains were more selective than those for aspartate and glutamate. In neuroleptic-treated control brains, levels of aspartate, glutamate, and glycine were found to be increased.
The changes in levels of aspartate, glutamate, NAAG, and NAALADase are prominent in the prefrontal and hippocampal regions, where previous neuropathological studies of schizophrenic brains demonstrate consistent changes. These findings support the hypothesis that schizophrenia results from a hypofunction of certain glutamatergic neuronal systems. They also suggest that the therapeutic efficacy of neuroleptics may be related to increased glutamatergic activity.
有假说认为精神分裂症是由谷氨酸能神经元功能减退所致。精神分裂症患者脑脊液中谷氨酸浓度降低以及谷氨酸受体拮抗剂可引发精神症状的研究结果支持了这一假说。N-乙酰天门冬氨酰谷氨酸（NAAG）是一种高度集中于谷氨酸能神经元的神经肽，可在N-甲基-D-天门冬氨酸受体处拮抗谷氨酸的作用。此外，NAAG可被一种特定的肽酶——N-乙酰-α-连接酸性二肽酶（NAALADase）裂解为谷氨酸和N-乙酰天门冬氨酸。为验证精神分裂症的谷氨酸能假说，我们研究了精神分裂症患者、接受抗精神病药物治疗的对照者以及正常个体尸检大脑中与NAAG相关的谷氨酸能变量，特别关注前额叶皮质和海马体。
对来自三个不同组（精神分裂症患者、接受抗精神病药物治疗的对照者和正常对照者）的冷冻脑组织的不同区域进行检测，以确定NAAG、N-乙酰天门冬氨酸、NAALADase以及包括天门冬氨酸和谷氨酸在内的几种氨基酸的水平。
我们的研究表明，大脑中天门冬氨酸、谷氨酸和NAAG的水平以及NAALADase活性发生了改变。精神分裂症患者大脑中NAAG水平升高，NAALADase活性和谷氨酸水平降低。值得注意的是，精神分裂症患者大脑中NAAG水平和NAALADase活性的变化比天门冬氨酸和谷氨酸的变化更具选择性。在接受抗精神病药物治疗的对照者大脑中，发现天门冬氨酸、谷氨酸和甘氨酸水平升高。
天门冬氨酸、谷氨酸、NAAG和NAALADase水平的变化在前额叶和海马体区域较为显著，此前对精神分裂症患者大脑的神经病理学研究也显示出一致的变化。这些发现支持了精神分裂症是由某些谷氨酸能神经元系统功能减退所致的假说。它们还表明，抗精神病药物的治疗效果可能与谷氨酸能活性增加有关。
