Memantine Improves Depressive-like Behaviors via Kir6.1 Channel Inhibition in Olfactory Bulbectomized Mice

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.