State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Shanxi Key Laboratory of Chinese Medicine Encephalopathy, Shanxi University of Chinese Medicine, Jinzhong, 030619, China.
Acta Pharmacol Sin. 2021 Jun;42(6):848-860. doi: 10.1038/s41401-020-00536-w. Epub 2020 Oct 7.
Sustained elevation of corticosterone (CORT) is one of the common causes of aging and major depression disorder. However, the role of elevated CORT in late life depression (LLD) has not been elucidated. In this study, 18-month-old female rats were subjected to bilateral adrenalectomy or sham surgery. Their CORT levels in plasma were adjusted by CORT replacement and the rats were divided into high-level CORT (H-CORT), low-level CORT (L-CORT), and Sham group. We showed that L-CORT rats displayed attenuated depressive symptoms and memory defects in behavioral tests as compared with Sham or H-CORT rats. Furthermore, we showed that glutamatergic transmission was enhanced in L-CORT rats, evidenced by enhanced population spike amplitude (PSA) recorded from the dentate gyrus of hippocampus in vivo and increased glutamate release from hippocampal synaptosomes caused by high frequency stimulation or CORT exposure. Intracerebroventricular injection of an enzymatic glutamate scavenger system, glutamic-pyruvic transmine (GPT, 1 μM), significantly increased the PSA in Sham rats, suggesting that extracelluar accumulation of glutamate might be the culprit of impaired glutamatergic transmission, which was dependent on the uptake by Glt-1 in astrocytes. We revealed that hippocampal Glt-1 expression level in the L-CORT rats was much higher than in Sham and H-CORT rats. In a gradient neuron-astrocyte coculture, we found that the expression of Glt-1 was decreased with the increase of neural percentage, suggesting that impairment of Glt-1 might result from the high level of CORT contributed neural damage. In sham rats, administration of DHK that inhibited Glt-1 activity induced significant LLD symptoms, whereas administration of RIL that promoted glutamate uptake significantly attenuated LLD. All of these results suggest that glutamatergic transmission impairment is one of important pathogenesis in LLD induced by high level of CORT, which provide promising clues for the treatment of LLD.
皮质酮（CORT）水平持续升高是衰老和重度抑郁症的常见原因之一。然而，升高的 CORT 在老年抑郁症（LLD）中的作用尚未阐明。在这项研究中，18 个月大的雌性大鼠接受了双侧肾上腺切除术或假手术。通过 CORT 替代来调节它们血浆中的 CORT 水平，然后将大鼠分为高水平 CORT（H-CORT）、低水平 CORT（L-CORT）和假手术组。我们发现与假手术或 H-CORT 大鼠相比，L-CORT 大鼠在行为测试中表现出抑郁症状和记忆缺陷减轻。此外，我们发现 L-CORT 大鼠的谷氨酸能传递增强，这表现在海马齿状回体内记录的群体峰电位幅度（PSA）增强，以及高频刺激或 CORT 暴露引起的海马突触小体谷氨酸释放增加。脑室内注射酶促谷氨酸清除系统谷氨酸-丙酮酸转氨酸（GPT，1 μM）可显著增加假手术大鼠的 PSA，表明细胞外谷氨酸的积累可能是谷氨酸能传递受损的罪魁祸首，这依赖于星形胶质细胞中 Glt-1 的摄取。我们揭示了 L-CORT 大鼠海马中的 Glt-1 表达水平远高于假手术和 H-CORT 大鼠。在梯度神经元-星形胶质细胞共培养物中，我们发现 Glt-1 的表达随着神经元百分比的增加而降低，表明 Glt-1 的损伤可能是由于高水平 CORT 导致的神经损伤所致。在假手术大鼠中，抑制 Glt-1 活性的 DHK 给药会导致明显的 LLD 症状，而促进谷氨酸摄取的 RIL 给药则显著减轻了 LLD。所有这些结果表明，谷氨酸能传递损伤是由高水平 CORT 引起的 LLD 的重要发病机制之一，为 LLD 的治疗提供了有希望的线索。
