Bay Zoltán Foundation for Applied Research-BAYGEN Institute, Derkovits Avenue 2, Szeged H-6726, Hungary.
Neurochem Int. 2011 Dec;59(8):1109-22. doi: 10.1016/j.neuint.2011.10.008. Epub 2011 Oct 25.
Impairments of cellular plasticity appear to underlie the pathophysiology of major depression. Recently, elevated levels of phosphorylated AMPA receptor were implicated in the antidepressant effect of various drugs. Here, we investigated the effects of an antidepressant, Tianeptine, on synaptic function and GluA1 phosphorylation using murine hippocampal slices and in vivo single-unit recordings. Tianeptine, but not imipramine, increased AMPA receptor-mediated neuronal responses both in vitro and in vivo, in a staurosporine-sensitive manner. Paired-pulse ratio was unaltered by Tianeptine, suggesting a postsynaptic site of action. Tianeptine, 10 μM, enhanced the GluA1-dependent initial phase of LTP, whereas 100 μM impaired the latter phases, indicating a critical role of GluA1 subunit phosphorylation in the excitation. Tianeptine rapidly increased the phosphorylation level of Ser(831)-GluA1 and Ser(845)-GluA1. Using H-89 and KN-93, we show that the activation of both PKA and CaMKII is critical in the effect of Tianeptine on AMPA responses. Moreover, the phosphorylation states of Ser(217/221)-MEK and Thr(183)/Tyr(185)-p42MAPK were increased by Tianeptine and specific kinase blockers of the MAPK pathways (PD 98095, SB 203580 and SP600125) prevented the effects of Tianeptine. Overall these data suggest that Tianeptine potentiates several signaling cascades associated with synaptic plasticity and provide further evidence that a major mechanism of action for Tianeptine is to act as an enhancer of glutamate neurotransmission via AMPA receptors.
细胞可塑性的损伤似乎是重度抑郁症病理生理学的基础。最近，磷酸化 AMPA 受体水平升高与各种药物的抗抑郁作用有关。在这里，我们使用鼠海马切片和体内单细胞记录研究了抗抑郁药噻奈普汀对突触功能和 GluA1 磷酸化的影响。噻奈普汀而非丙咪嗪以 staurosporine 敏感的方式增加了体外和体内 AMPA 受体介导的神经元反应。噻奈普汀对成对脉冲比没有影响，提示其作用部位在突触后。噻奈普汀（10μM）增强了 GluA1 依赖性 LTP 的初始阶段，而 100μM 则损害了后期阶段，表明 GluA1 亚基磷酸化在兴奋中起着关键作用。噻奈普汀可迅速增加 Ser(831)-GluA1 和 Ser(845)-GluA1 的磷酸化水平。使用 H-89 和 KN-93，我们表明 PKA 和 CaMKII 的激活对噻奈普汀对 AMPA 反应的影响至关重要。此外，噻奈普汀还增加了 Ser(217/221)-MEK 和 Thr(183)/Tyr(185)-p42MAPK 的磷酸化状态，MAPK 途径的特定激酶抑制剂（PD 98095、SB 203580 和 SP600125）可阻止噻奈普汀的作用。总的来说，这些数据表明噻奈普汀增强了与突触可塑性相关的几个信号级联，进一步证明噻奈普汀的主要作用机制是通过 AMPA 受体增强谷氨酸能神经传递。
