Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients
Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients
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DOI：
10.1176/appi.ajp.159.7.1165
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发表时间：
2002-07-01
影响因子：
17.7
通讯作者：
Haroutunian, V
中科院分区：
文献类型：
--
作者：
Gluck, MR;Thomas, RG;Haroutunian, V
目的：药理学、临床和尸检研究表明精神分裂症患者的γ-氨基丁酸（GABA）能和谷氨酸能功能改变。背外侧前额叶皮层是异常的一个关键部位。神经递质改变的确切神经化学机制，如脑下垂体痛或GABA功能障碍，还没有很好地理解。本研究调查了精神分裂症患者脑标本中GABA和谷氨酸代谢的关键生化元素。9个主要的GABA和谷氨酸相关的代谢酶的活动进行了测量，同时在背外侧前额叶皮层的前死亡评估和神经病理学特征的精神分裂症和对照科目。精神分裂症，阿尔茨海默病，和正常的非精神病对照受试者进行了测定，以确定活动的主要谷氨酸和GABA-代谢酶包括谷氨酰胺合成酶、谷氨酸脱氢酶、α-酮戊二酸脱氢酶、磷酸活化的天冬氨酸氨基转移酶、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、谷氨酸脱羧酶、GABA-转氨酶和琥珀酸半醛脱氢酶。谷氨酸脱羧酶活性是对照组的2倍，磷酸活化转氨酶活性是对照组的4倍。在死后间隔，组织pH值，磷酸活化转氨酶的抑制和药物作用的差异不能解释的差异，磷酸活化转氨酶和谷氨酸脱羧酶活性的差异，从阿尔茨海默氏症患者的等效标本中没有观察到。其余的酶的活动是不变的。结论：更大的磷酸盐激活的谷氨酸脱羧酶和谷氨酸脱羧酶的活动，具体到精神分裂症患者，提供了额外的生化证据，背外侧前额叶皮层谷氨酸和GABA的代谢在精神分裂症受试者的改变。这些更大的活动与精神分裂症中谷氨酸能/GABA能状态失调的模型一致。
Objective: Pharmacological, clinical, and postmortem studies suggest altered -aminobutyric acid (GABA)-ergic and glutamatergic function in patients with schizophrenia. The dorsolateral prefrontal cortex is one key locus of abnormality. The precise neurochemical mechanisms underlying neurotransmitter alterations, such as hypoglutamatergia or GABA dysfunction, are not well understood. This study investigated key biochemical elements of GABA and glutamate metabolism in brain specimens from schizophrenic patients. The activities of nine principal GABA and glutamate-associated metabolic enzymes were measured concurrently in the dorsolateral prefrontal cortex of antemortem-assessed and neuropathologically characterized schizophrenic and comparison subjects.Method: Postmortem dorsolateral prefrontal cortex specimens from schizophrenia, Alzheimer's disease, and normal non-psychiatric comparison subjects were assayed to determine activities of the principal glutamate and GABA-metabolizing enzymes glutamine synthetase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, phosphate-activated glutaminase, alanine aminotransferase, aspartate aminotransferase, glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase.Results: Glutamic acid decarboxylase activities were twofold greater and phosphate-activated glutaminase activities were fourfold greater in the schizophrenic group than in the comparison group. Differences in postmortem interval, tissue pH, inhibition of phosphate-activated glutaminase, and medication effects could not account for the differences, Differences in phosphate-activated glutaminase and glutamic acid decarboxylase activities in equivalent specimens from Alzheimer's patients were not observed. The activities of the remaining enzymes were unchanged.Conclusions: Greater phosphate-activated glutaminase and glutamic acid decarboxylase activities, specific to schizophrenia patients, provide additional biochemical evidence that dorsolateral prefrontal cortex glutamate and GABA metabolism is altered in schizophrenic subjects. These greater activities are consistent with models of a dysregulated glutamatergic/GABA-ergic state in schizophrenia.