Brown Samara J, Brown Amelia M, Purves-Tyson Tertia D, Huang Xu-Feng, Shannon Weickert Cynthia, Newell Kelly A
School of Medical, Indigenous and Health Sciences and Molecular Horizons, University of Wollongong, Wollongong, New South Wales, 2522, Australia; Illawarra Health and Medical Research Institute, Wollongong, New South Wales, 2522, Australia.
Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, New South Wales, 2031, Australia.
J Psychiatr Res. 2023 Apr;160:204-209. doi: 10.1016/j.jpsychires.2023.02.017. Epub 2023 Feb 16.
The glutamatergic system may be central to the neurobiology and treatment of major depressive disorder (MDD) and psychosis. Despite the success of N-methyl-D-aspartate receptor (NMDAR) antagonists for the treatment of MDD, little is known regarding the expression of these glutamate receptors in MDD. In this study we measured gene expression, via qRT-PCR, of the major NMDAR subunits, in the anterior cingulate cortex (ACC) in MDD subjects with and without psychosis, and non-psychiatric controls. Overall, GRIN2B mRNA was increased in both MDD with (+32%) and without psychosis (+40%) compared to controls along with a trend increase in GRIN1 mRNA in MDD overall (+24%). Furthermore, in MDD with psychosis there was a significant decrease in the GRIN2A:GRIN2B mRNA ratio (-19%). Collectively these results suggest dysfunction of the glutamatergic system at the gene expression level in the ACC in MDD. Increased GRIN2B mRNA in MDD, along with an altered GRIN2A:GRIN2B ratio in psychotic depression, suggests a disruption to NMDAR composition could be present in the ACC in MDD; this could lead to enhanced signalling via GluN2B-containing NMDARs and greater potential for glutamate excitotoxicity in the ACC in MDD. These results support future research into GluN2B antagonist-based treatments for MDD.
谷氨酸能系统可能在重度抑郁症（MDD）和精神病的神经生物学及治疗中起核心作用。尽管N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂在治疗MDD方面取得了成功，但对于这些谷氨酸受体在MDD中的表达情况却知之甚少。在本研究中，我们通过定量逆转录聚合酶链反应（qRT-PCR）测量了有或无精神病的MDD患者以及非精神科对照者前扣带回皮质（ACC）中主要NMDAR亚基的基因表达。总体而言，与对照组相比，伴有精神病（增加32%）和不伴有精神病（增加40%）的MDD患者GRIN2B mRNA均增加，且MDD患者总体GRIN1 mRNA有增加趋势（增加24%）。此外，伴有精神病的MDD患者中GRIN2A:GRIN2B mRNA比值显著降低（降低19%）。这些结果共同表明MDD患者ACC中谷氨酸能系统在基因表达水平存在功能障碍。MDD患者GRIN2B mRNA增加，以及精神病性抑郁症患者GRIN2A:GRIN2B比值改变，提示MDD患者ACC中可能存在NMDAR组成的破坏；这可能导致通过含GluN2B的NMDAR增强信号传导，并增加MDD患者ACC中谷氨酸兴奋性毒性的可能性。这些结果支持未来对基于GluN2B拮抗剂的MDD治疗进行研究。
