Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Neuropsychopharmacology. 2018 Jan;43(2):302-312. doi: 10.1038/npp.2017.199. Epub 2017 Aug 30.
The mechanisms underlying chronic stress-induced dysfunction of glutamatergic transmission that contribute to helplessness-associated depressive disorder are unknown. We investigated the relationship of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and stress, and the neuroplastic changes of stress-induced depression-like behavior in the ventrolateral periaqueductal gray (vlPAG). We conducted whole-cell patch-clamp electrophysiological recordings in the vlPAG neurons. Depression-like behavior was assayed using tail suspension test and sucrose preference test. Surface and cytosolic glutamate receptor 1 (GluR1) AMPA receptor expression was analyzed using western blotting. Phosphorylated GluR1 expression was quantified using western blotting and immunohistochemical analysis. Unpredictable inescapable foot shock stress caused reduction in glutamatergic transmission originating from both presynaptic and postsynaptic loci in the vlPAG that was associated with behavioral despair and anhedonia in chronic stress-induced depression. Pharmacological inhibition of GluR1 function in the vlPAG caused depression-like behavior. Diminished glutamatergic transmission was due to reduced glutamate release presynaptically and enhanced GluR1-endocytosis from the cell surface postsynaptically. Chronic stress-induced neuroplastic changes and maladaptive behavior were reversed and mimicked by administration of glucocorticoid receptor (GR) antagonist and agonist, respectively. However, chronic stress did not affect γ-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission in the vlPAG. These results demonstrate that depression-like behavior is associated with remarkable reduction in glutamatergic, but not GABAergic, transmission in the vlPAG. These neuroplastic changes and maladaptive behavior are attributed to GR-dependent mechanisms. As reduced GluR1-associated responses in the vlPAG contribute to chronic stress-induced neuroplastic changes, this cellular mechanism may be a critical component in the pathogenesis of stress-associated neuropsychiatric disorders.
慢性应激引起的谷氨酸能传递功能障碍的机制导致无助相关的抑郁障碍，但尚不清楚其机制。我们研究了α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体与应激的关系，以及应激诱导的抑郁样行为在腹外侧导水管周围灰质（vlPAG）中的神经可塑性变化。我们在 vlPAG 神经元中进行了全细胞膜片钳电生理记录。使用悬尾试验和蔗糖偏好试验检测抑郁样行为。使用 Western blot 分析细胞表面和细胞溶质谷氨酸受体 1（GluR1）AMPA 受体表达。使用 Western blot 和免疫组织化学分析定量磷酸化 GluR1 表达。不可预测的不可逃避的足部电击应激导致 vlPAG 中来自突触前和突触后部位的谷氨酸能传递减少，这与慢性应激诱导的抑郁中的行为绝望和快感缺失有关。vlPAG 中的 GluR1 功能的药理学抑制导致抑郁样行为。谷氨酸能传递减少是由于突触前谷氨酸释放减少和突触后 GluR1 内吞增加所致。慢性应激诱导的神经可塑性变化和适应不良行为分别被糖皮质激素受体（GR）拮抗剂和激动剂逆转和模拟。然而，慢性应激并不影响 vlPAG 中的γ-氨基丁酸（GABA）介导的抑制性突触传递。这些结果表明，抑郁样行为与 vlPAG 中谷氨酸能传递而不是 GABA 能传递的显著减少有关。这些神经可塑性变化和适应不良行为归因于 GR 依赖性机制。由于 vlPAG 中 GluR1 相关反应的减少导致慢性应激诱导的神经可塑性变化，因此这种细胞机制可能是应激相关神经精神疾病发病机制的关键组成部分。
