Role of group II metabotropic glutamate receptors in cognitive decline caused by multiple administrations of ketamine in mice: the relationship with hippocampal GSK3β expression

Objective To evaluate the role of group Ⅱ metabotropic glutamate receptors (mGluRs) in cognitive decline caused by multiple administrations of ketamine in mice and the relationship with hippocampal glycogen synthase kinase-3 beta (GSK-3β) expression. Methods Forty-five SPF healthy female C57BL/6 mice, aged 6-8 weeks, weighing 20-30 g, were randomized into 3 groups (n=15 each) using a random number table method: control group (group C), ketamine group (group K) and mGluR agonist LY354740 group (group L+ K). In K and L+ K groups, ketamine 30 mg/kg was intraperitoneally injected three times a day at an 30-min interval for 14 consecutive days.LY354740 was intraperitoneally injected at 30 min before the first injection of ketamine in group L+ K.The equal volume of normal saline was given instead in group C. Morris water maze test was performed the day after the last administration.The mice were then sacrificed, and hippocampi were harvested to determine the expression of GSK3β, NR2A and postsynaptic density protein 95 (PSD95) by Western blot. Results Compared with group C, the escape latency was significantly prolonged, the time of staying at the original platform quadrant was shortened, the frequency of crossing the original platform was decreased, the expression of GSK3β and NR2A was up-regulated, and the expression of PSD95 was down-regulated in group K (P 0.05). Compared with group K, the escape latency was significantly shortened, the time of staying at the original platform quadrant was prolonged, the frequency of crossing the original platform was increased, the expression of GSK3β and NR2A was down-regulated, and the expression of PSD95 was up-regulated in group L+ K (P<0.05). Conclusion Group Ⅱ mGluRs are involved in the process of cognitive decline caused by multiple administrations of ketamine in mice, which is associated with up-regulated expression of hippocampal GSK-3β. Key words: Receptors, glutamate; Ketamine; Cognition disorders; Glycogen synthase kinase 3