Shifts in Excitatory/Inhibitory Balance by Juvenile Stress: A Role for Neuron-Astrocyte Interaction in the Dentate Gyrus
Shifts in Excitatory/Inhibitory Balance by Juvenile Stress: A Role for Neuron-Astrocyte Interaction in the Dentate Gyrus
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DOI：
10.1002/glia.22970
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发表时间：
2016-06-01
期刊：
影响因子：
6.2
通讯作者：
Stork, Oliver
中科院分区：
文献类型：
--
作者：
Albrecht, Anne;Ivens, Sebastian;Stork, Oliver
童年创伤是与压力相关的精神病理学（例如创伤后应激障碍或晚年抑郁症）发展的一个明确的危险因素。可以通过青少年应激（JS）方案在啮齿类动物中模拟童年逆境，从而导致成年后应对压力挑战的能力受损。在当前的研究中，我们利用激光显微切割和定量实时聚合酶链反应研究了 JS 对齿状回 (DG) 亚层中谷氨酸和γ-氨基丁酸 (GABA) 摄取和周转的分子因子表达的长期影响。我们观察到 JS 后介导星形胶质细胞谷氨酸和 GABA 摄取和降解的因子 mRNA 表达水平降低。这些变化在背侧 DG 颗粒细胞层而非腹侧 DG 颗粒细胞层中明显观察到，表明星形胶质细胞 GABA 和谷氨酸代谢发生持久变化，可能影响背侧 DG 网络活动。事实上，我们观察到 JS 后背侧 DG 在短刺激间隔下对配对脉冲刺激的抑制增加，且缺乏促进作用，而基础突触传递或长期可塑性形式没有明显变化。通过药理学阻断幼稚动物中的星形胶质细胞 GABA 转运蛋白 GAT-3 来模拟配对脉冲反应的转变。因此，在幼年应激大鼠的背侧颗粒细胞层的蛋白质水平上证实了GAT-3的表达水平降低。总之，这些数据表明，JS 导致的背侧 DG 网络活性的兴奋/抑制平衡发生了持久的转变，这似乎是由星形胶质细胞 GABA 摄取减少介导的。
Childhood trauma is a well-described risk factor for the development of stress-related psychopathology such as posttraumatic stress disorder or depression later in life. Childhood adversity can be modeled in rodents by juvenile stress (JS) protocols, resulting in impaired coping with stressful challenges in adulthood. In the current study, we investigated the long-lasting impact of JS on the expression of molecular factors for glutamate and gamma-aminobutyric acid (GABA) uptake and turnover in sublayers of the dentate gyrus (DG) using laser microdissection and quantitative real-time polymerase chain reaction. We observed reduced mRNA expression levels after JS for factors mediating astrocytic glutamate and GABA uptake and degradation. These alterations were prominently observed in the dorsal but not ventral DG granule cell layer, indicating a lasting change in astrocytic GABA and glutamate metabolism that may affect dorsal DG network activity. Indeed, we observed increased inhibition and a lack of facilitation in response to paired-pulse stimulation at short interstimulus intervals in the dorsal DG after JS, while no alterations were evident in basal synaptic transmission or forms of long-term plasticity. The shift in paired-pulse response was mimicked by pharmacologically blocking the astrocytic GABA transporter GAT-3 in naive animals. Accordingly, reduced expression levels of GAT-3 were confirmed at the protein level in the dorsal granule cell layer of rats stressed in juvenility. Together, these data demonstrate a lasting shift in the excitatory/inhibitory balance of dorsal DG network activity by JS that appears to be mediated by decreased GABA uptake into astrocytes.