Aberrant depressive-like behaviors in olfactory bulbectomized (OBX) mice have been documented by previous studies. Here, we show that memantine enhances adult neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors via inhibition of the ATP-sensitive potassium (K_ATP) channel in OBX mice. Treatment with memantine (1–3 mg/kg; per os (p.o.)) for 14 days significantly improved depressive-like behaviors in OBX mice, as assessed using the tail-suspension and forced-swim tests. Treatment with memantine also increased the number of BrdU-positive neurons in the DG of OBX mice. In the immunoblot analysis, memantine significantly increased phosphorylation of CaMKIV (Thr-196) and Akt (Ser-473), but not ERK (Thr-202/Tyr-204), in the DG of OBX mice. Furthermore, phosphorylation of GSK3β (Ser-9) and CREB (Ser-133), and BDNF protein expression levels increased in the DG of OBX mice, possibly accounting for the increased adult neurogenesis owing to Akt activation. In contrast, both the improvement of depressive-like behaviors and increase in BrdU-positive neurons in the DG following treatment with memantine were unapparent in OBX-treated Kir6.1 heterozygous (+/-) mice but not OBX-treated Kir6.2 heterozygous (+/-) mice. Furthermore, the increase in CaMKIV (Thr-196) and Akt (Ser-473) phosphorylation and BDNF protein expression levels was not observed in OBX-treated Kir6.1 +/- mice. Overall, our study shows that memantine improves OBX-induced depressive-like behaviors by increasing adult neurogenesis in the DG via Kir6.1 channel inhibition.

先前的研究已经记录了嗅球切除 (OBX) 小鼠的异常抑郁样行为。在这里，我们表明美金刚可增强海马齿状回 (DG) 颗粒下区的成人神经发生，并通过抑制 ATP 敏感钾 (K _{ATP ) 来改善抑郁样行为。}) OBX 小鼠中的通道。用美金刚（1-3 mg/kg；per os (po)）治疗 14 天显着改善了 OBX 小鼠的抑郁样行为，正如使用悬尾和强迫游泳测试所评估的那样。美金刚处理还增加了 OBX 小鼠 DG 中 BrdU 阳性神经元的数量。在免疫印迹分析中，美金刚显着增加了 OBX 小鼠 DG 中 CaMKIV (Thr-196) 和 Akt (Ser-473) 的磷酸化，但不增加 ERK (Thr-202/Tyr-204) 的磷酸化。此外，OBX 小鼠的 DG 中 GSK3β (Ser-9) 和 CREB ​​(Ser-133) 的磷酸化和 BDNF 蛋白表达水平增加，这可能是由于 Akt 激活导致成人神经发生增加的原因。相比之下，在 OBX 处理的 Kir6.1 杂合子 (+/-) 小鼠中，抑郁样行为的改善和 DG 中 BrdU 阳性神经元的增加在 OBX 处理的 Kir6.1 杂合子 (+/-) 小鼠中不明显，但在 OBX 处理的 Kir6.2 杂合子 (+/ -） 老鼠。此外，在 OBX 处理的 Kir6.1 +/- 小鼠中未观察到 CaMKIV (Thr-196) 和 Akt (Ser-473) 磷酸化和 BDNF 蛋白表达水平的增加。总体而言，我们的研究表明，美金刚通过抑制 Kir6.1 通道增加 DG 中的成人神经发生，从而改善 OBX 诱导的抑郁样行为。