Novel synergistic treatment for depression: involvement of GSK3β-regulated AMPA receptors in the prefrontal cortex of mice
Novel synergistic treatment for depression: involvement of GSK3β-regulated AMPA receptors in the prefrontal cortex of mice
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DOI：
10.1093/cercor/bhad299
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发表时间：
2023-08-11
期刊：
影响因子：
3.7
通讯作者：
Wang，Chuang
中科院分区：
文献类型：
--
作者：
Guo，Lei;Wang，Shuzhuo;Wang，Chuang
已有证据表明糖原合成酶激酶3β介导的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体在抑郁症的转运中起重要作用。考虑到前额叶皮质α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体激活的抗抑郁作用，我们推测糖原合成酶激酶3β诱导的前额叶皮质α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体功能的改变参与了抑郁的发生。在此，我们证实了在表现出抑郁样行为的慢性社会失败应激模型小鼠的前额叶皮质中，磷酸化糖原合成酶激酶3β和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的亚单位GluA1的水平降低。我们随后发现，糖原合成酶激酶3β(p.S9A)点突变下调了小鼠的GluA1并诱导了抑郁样行为，而α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体激动剂PF-4778574(2 mg/kg)不能逆转这种分子变化。另一方面，PF-4778574的抗抑郁作用呈剂量依赖关系，单独给予较低剂量的PF-4778574(0.5 mg/kg)或糖原合成酶3β抑制剂SB216763(5 mg/kg和10 mg/kg)均不能引起抗抑郁作用。相比之下，PF-4778574(0.5 mg/kg)和SB216763(10 mg/kg)联合治疗的抗抑郁效果与PF-4778574(2 mg/kg)相似。我们的结果表明，糖原合成酶激酶3β诱导的前额叶皮质α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体功能障碍是抑郁症的关键机制之一，小剂量PF-4778574与SB216763联合治疗抑郁症具有潜在的新的协同治疗潜力。
Previous evidence has suggested a vital role of glycogen synthase kinase 3β-mediated α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors trafficking in depression. Considering the antidepressant effect of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors activation in the prefrontal cortex, we hypothesized that glycogen synthase kinase 3β-induced alterations in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors function in the prefrontal cortex participate in depression. Herein, we confirmed that the levels of phosphorylated glycogen synthase kinase 3β and GluA1, the latter being a subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, were decreased in the prefrontal cortex of the chronic social defeat stress model mice presenting with depressive-like behaviors. We then found that a glycogen synthase kinase 3β (p.S9A) point mutation downregulated GluA1 and induced depressive-like behaviors in mice, whereas an agonist of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, PF-4778574 (2 mg/kg) did not reversed the molecular changes. On the other hand, the antidepressant effect of PF-4778574 was dose dependent, and the single administration of PF-4778574 at a lower dose (0.5 mg/kg) or of the glycogen synthase kinase 3β inhibitor SB216763 (5 and 10 mg/kg) did not evoke an antidepressant effect. In contrast, co-treatment with PF-4778574 (0.5 mg/kg) and SB216763 (10 mg/kg) led to antidepressant effects similar to those of PF-4778574 (2 mg/kg). Our results suggest that glycogen synthase kinase 3β-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors dysfunction in the prefrontal cortex is one of the key mechanisms of depression, and the combination of a lower dose of PF-4778574 with SB216763 shows potential as a novel synergistic treatment for depression.