Low corticosterone levels attenuate late life depression and enhance glutamatergic neurotransmission in female rats
Low corticosterone levels attenuate late life depression and enhance glutamatergic neurotransmission in female rats
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低皮质酮水平可减轻雌性大鼠晚年抑郁症并增强谷氨酸能神经传递
DOI：
10.1038/s41401-020-00536-w
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发表时间：
2020-10-07
影响因子：
8.2
通讯作者：
Chen, Nai-hong
中科院分区：
文献类型：
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作者：
Chu, Shi-feng;Zhang, Zhao;Chen, Nai-hong
皮质酮(CORT)持续升高是引起衰老和抑郁症的常见原因之一。然而，皮质醇升高在晚年抑郁(LLD)中的作用尚未阐明。在这项研究中，18月龄雌性大鼠接受了双侧肾上腺切除或假手术。用皮质醇替代法调整大鼠血浆皮质醇水平，将大鼠分为高水平皮质醇(H-CORT)组、低水平皮质醇(L-皮质醇)组和假手术组。我们在行为学测试中发现，与Sham或H-Cort大鼠相比，L-Cort大鼠的抑郁症状和记忆缺陷都有所减轻。此外，我们还发现，L-皮质醇大鼠的谷氨酸能传递增强，表现为在体海马齿状回记录的群体峰幅度(PSA)增加，以及高频刺激或皮质醇暴露引起的海马突触体谷氨酸释放增加。脑室注射酶促谷氨酸清除剂系统谷丙转氨酶(GPT，1 μM)可显著增加假手术大鼠的PSA，提示细胞外谷氨酸蓄积可能是谷氨酸能传递受损的罪魁祸首，其作用依赖于星形胶质细胞对谷氨酸的摄取。我们发现L-Cort组大鼠海马区GLT-1的表达水平明显高于Sham和H-Cort组大鼠。在神经元-星形胶质细胞共培养中，我们发现GLT-1的表达随着神经元百分比的增加而减少，提示GLT-1的损伤可能是由于高水平的皮质醇引起的神经损伤所致。在假手术大鼠中，给予抑制GLT-1活性的DHK可引起显著的LLD症状，而给予促进谷氨酸摄取的RIL可显著减轻LLD。这些结果提示谷氨酸能传递障碍是皮质醇水平升高所致LLD的重要发病机制之一，为LLD的治疗提供了新的线索。
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.