O'Donovan Sinead M, Shan Dan, Wu Xiaojun, Choi Jae Hyuk, McCullumsmith Robert E
Department of Neuroscience, University of Toledo, Toledo, OH, USA.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Schizophr Bull. 2025 Mar 14;51(2):531-542. doi: 10.1093/schbul/sbae092.
Schizophrenia (SCZ) is a serious mental illness with complex pathology, including abnormalities in the glutamate system. Glutamate is rapidly removed from the synapse by excitatory amino acid transporters (EAATs). Changes in the expression and localization of the primary glutamate transporter EAAT2 are found in the brain in central nervous system (CNS) disorders including SCZ. We hypothesize that neuronal expression and function of EAAT2 are increased in the frontal cortex in subjects diagnosed with SCZ.
EAAT2 protein expression and glutamate transporter function were assayed in synaptosome preparations from the dorsolateral prefrontal cortex (DLPFC) of SCZ subjects and age- and sex-matched nonpsychiatrically ill controls. EAAT2 splice variant transcript expression was assayed in enriched populations of neurons and astrocytes from the DLPFC. Pathway analysis of publicly available transcriptomic datasets was carried out to identify biological changes associated with EAAT2 perturbation in different cell types.
We found no significant changes in EAAT2 protein expression or glutamate uptake in the DLPFC in SCZ subjects compared with controls (n = 10/group). Transcript expression of EAAT2 and signaling molecules associated with EAAT2b trafficking (CaMKIIa and DLG1) were significantly altered in enriched populations of astrocytes and pyramidal neurons (P < .05) in SCZ (n = 16/group). These changes were not associated with antipsychotic medications. Pathway analysis also identified cell-type-specific enrichment of biological pathways associated with perturbation of astrocyte (immune pathways) and neuronal (metabolic pathways) EAAT2 expression.
Overall, these data support the growing body of evidence for the role of dysregulation of the glutamate system in the pathophysiology of SCZ.
精神分裂症（SCZ）是一种具有复杂病理机制的严重精神疾病，包括谷氨酸系统异常。谷氨酸通过兴奋性氨基酸转运体（EAATs）迅速从突触中清除。在包括SCZ在内的中枢神经系统（CNS）疾病中，主要谷氨酸转运体EAAT2的表达和定位会发生变化。我们假设，被诊断为SCZ的受试者额叶皮质中EAAT2的神经元表达和功能会增加。
在SCZ受试者以及年龄和性别匹配的非精神疾病对照者的背外侧前额叶皮质（DLPFC）的突触体标本中检测EAAT2蛋白表达和谷氨酸转运体功能。在DLPFC的富集神经元和星形胶质细胞群体中检测EAAT2剪接变体转录本表达。对公开可用的转录组数据集进行通路分析，以确定与不同细胞类型中EAAT2扰动相关的生物学变化。
与对照组（每组n = 10）相比，我们发现SCZ受试者DLPFC中EAAT2蛋白表达或谷氨酸摄取没有显著变化。在SCZ组（每组n = 16）的富集星形胶质细胞和锥体神经元群体中，EAAT2的转录表达以及与EAAT2b转运相关的信号分子（CaMKIIa和DLG1）发生了显著改变（P <.05）。这些变化与抗精神病药物无关。通路分析还确定了与星形胶质细胞（免疫通路）和神经元（代谢通路）EAAT2表达扰动相关的生物学通路在细胞类型上的特异性富集。
总体而言，这些数据支持了越来越多的证据表明谷氨酸系统失调在SCZ病理生理学中的作用。
