The Role Of Hippocampal BDNF-p11 Signal Pathway In The Antidepressant-like Effects Of Ketamine

Objective:The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine can produce rapid, effective, and sustained antidepressant effects. Different molecular mechanisms, neural circuits, signal pathways, and special brain regions play some roles in the antidepressant effects of ketamine, however, the precise mechanism still remains unclear. Recent studies have shown that the small molecular protein pll plays a key role in the neuropathological mechanisms of depression, by facilitating the cell surface expression of many ion channels and 5-hydroxytryptamine (5-HT) receptors, and improving the neural regeneration. The mRNA and protein levels of p11 is decreased in the peripheral blood cells in depressed patients and the relevant regions in animal model of depression, moreover, the level of p11 can serve as an indicator for the prognosis of depressed patients. The brain-derived neurotrophic factor (BDNF), which plays a key role in the antidepressant-like activity of ketamine, has been proven to produce antidepressant effects by facilitating the hippocampal expression of p11 in both vivo and vitro. Therefore, we hypothesized that BDNF-p11 signal pathway contributes to the antidepressant-like effects of ketamine. This research will study the alterations and roles of BDNF and pll in the antidepressant-effects of ketamine and discuss the related mechanisms.Methods:The chronic unpredicted mild stress (CUMS) was used to set up a rat model of depression. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were performed to evaluate the depression-like behaviors of rats after intraperitoneal administration of ketamine (10 mg/kg) or a combination of ketamine (10 mg/kg) and ANA-12 (a selective tyrosine kinases (TrkB) antagonist,0.5 mg/kg). Three lentivirus vectors for p11 were constructed and screened by cultivation of hippocampal neurons in vitro. The most efficient lentivirus was selected and injected into the hippocampus to knockdown the expression of p11 and behavioral tests were preformed 10 days later. After behavioral tests, the hippocampus was separated and Western blotting was performed to determine the expression of BDNF and p11 in rat hippocampus.Results:Compared with the control group, the CUMS rats showed depression-like behaviors with the increased immobility time in the FST and the decreased sucrose preference percent in the SPT. The immobility time in the FST was decreased and the sucrose preference percent in the SPT was increased in the CUMS rats at 0.5 h and 72 h after ketamine administration, which had no significant difference compared with the control group, suggesting the rapid and sustained antidepressant effects of ketamine. Compared with the CUMS rats with ketamine administration alone, ANA-12 blocked the antidepressant effects of ketamine with increased immobility time in the FST and the decreased sucrose preference percent in the SPT in CUMS rats at 0.5 h and 72 h after the co-administration of ketamine and ANA-12, which had no significant difference compared with the CUMS rats receiving saline administration. All the treatments did not significantly affect the total distance of rats traveled in the OFT (P> 0.05). Compared with the control group, the hippocampal expression of BDNF and p11 was decreased significantly in the CUMS rats (P< 0.05). The hippocampal expression of BDNF was increased at 0.5 h and 72 h after ketamine administration in the CUMS rats and had no significant difference compared with the control group. However, the hippocampal expression of p11 was only increased at 72 h, but not 0.5 h, after ketamine administration in the CUMS rats (P< 0.05). Compared with the CUMS rats with ketamine administration alone, the hippocampal expression of p11 was decreased at 72 h after the co-administration of ketamine and ANA-12 (P < 0.05), which had no significant difference compared with the CUMS rats with saline administration (P> 0.05). Compared with the control group, the hippocampal injection of empty lentivirus in vivo had no significant difference in the immobility time and sucrose preference percent (P> 0.05). Compared with the rats with hippocampal injection of empty lentivirus, the hippocampal level of p11 was significantly decreased and the rats showed depression-like behaviors with the increased immobility time and decreased sucrose preference percent at 13 d after hippocampal injection of p11-lenti virus in vivo. Compared with saline administration, the rats with hippocampal injection of p11-lentivirus had no significant difference in the immobility time and sucrose preference percent after ketamine administration (P> 0.05), suggesting that knockdown of hippocampal p11 blocks the antidepressant-like effects of ketamine.Conclusions:The hippocampal BDNF-p11 signal pathway plays a key role in the sustained antidepressant activity of ketamine in the rat CUMS model of depression.