McCullumsmith R E, O'Donovan S M, Drummond J B, Benesh F S, Simmons M, Roberts R, Lauriat T, Haroutunian V, Meador-Woodruff J H
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama-Birmingham, Birmingham, AL, USA.
Mol Psychiatry. 2016 Jun;21(6):823-30. doi: 10.1038/mp.2015.148. Epub 2015 Sep 29.
Excitatory amino-acid transporters (EAATs) bind and transport glutamate, limiting spillover from synapses due to their dense perisynaptic expression primarily on astroglia. Converging evidence suggests that abnormalities in the astroglial glutamate transporter localization and function may underlie a disease mechanism with pathological glutamate spillover as well as alterations in the kinetics of perisynaptic glutamate buffering and uptake contributing to dysfunction of thalamo-cortical circuits in schizophrenia. We explored this hypothesis by performing cell- and region-level studies of EAAT1 and EAAT2 expression in the mediodorsal nucleus of the thalamus in an elderly cohort of subjects with schizophrenia. We found decreased protein expression for the typically astroglial-localized glutamate transporters in the mediodorsal and ventral tier nuclei. We next used laser-capture microdissection and quantitative polymerase chain reaction to assess cell-level expression of the transporters and their splice variants. In the mediodorsal nucleus, we found lower expression of transporter transcripts in a population of cells enriched for astrocytes, and higher expression of transporter transcripts in a population of cells enriched for relay neurons. We confirmed expression of transporter protein in neurons in schizophrenia using dual-label immunofluorescence. Finally, the pattern of transporter mRNA and protein expression in rodents treated for 9 months with antipsychotic medication suggests that our findings are not due to the effects of antipsychotic treatment. We found a compensatory increase in transporter expression in neurons that might be secondary to a loss of transporter expression in astrocytes. These changes suggest a profound abnormality in astrocyte functions that support, nourish and maintain neuronal fidelity and synaptic activity.
兴奋性氨基酸转运体（EAATs）结合并转运谷氨酸，由于其主要在星形胶质细胞上的突触周围密集表达，从而限制了突触间的递质外溢。越来越多的证据表明，星形胶质细胞谷氨酸转运体的定位和功能异常可能是一种疾病机制的基础，这种机制包括病理性谷氨酸外溢，以及突触周围谷氨酸缓冲和摄取动力学的改变，进而导致精神分裂症中丘脑 - 皮质回路功能障碍。我们通过对一组老年精神分裂症患者丘脑背内侧核中EAAT1和EAAT2表达进行细胞和区域水平的研究来探索这一假设。我们发现，在背内侧核和腹侧层核中，典型的星形胶质细胞定位的谷氨酸转运体的蛋白表达降低。接下来，我们使用激光捕获显微切割和定量聚合酶链反应来评估转运体及其剪接变体的细胞水平表达。在背内侧核中，我们发现在富含星形胶质细胞的细胞群体中转运体转录本表达较低，而在富含中继神经元的细胞群体中转运体转录本表达较高。我们使用双标记免疫荧光法在精神分裂症患者的神经元中证实了转运体蛋白的表达。最后，用抗精神病药物治疗9个月的啮齿动物中转运体mRNA和蛋白表达模式表明，我们的发现并非抗精神病治疗的结果。我们发现神经元中转运体表达有代偿性增加，这可能继发于星形胶质细胞中转运体表达的丧失。这些变化表明，在支持、滋养和维持神经元保真度及突触活动的星形胶质细胞功能方面存在严重异常。
