Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia

Recent studies have demonstrated that lithium has a neuroprotective effect against brain ischemia. Whether this effect is mediated by hippocampal neurogenesis remains unknown. The ERK (extracellular signal-regulated kinase) pathway plays an essential role in regulating neurogenesis. The present study was undertaken to investigate whether lithium regulates hippocampal neurogenesis by the ERK pathway and improves spatial learning and memory deficits in rats after ischemia. Rats were daily injected with lithium (1 mmol/kg) and 2 weeks later subjected to 15-min ischemia induced by four-vessel occlusion method. 5-bromo-2′-deoxyuridine (Brdu; 50 mg/kg) was administrated twice daily at postischemic day 6, or for 3 days from postischemic day 6 to 8. We found that lithium increased the ERK1/2 activation after ischemia by western blotting analysis. There was a significant increase in Brdu-positive cells in the hippocampal dentate gyrus after lithium treatment, compared with ischemia group at postischemic days 7 and 21; furthermore, the survival rate of Brdu-positive cells was elevated by lithium. Inhibition of the ERK1/2 activation by U0126 diminished these effects of lithium. The percentages of Brdu-positive cells that expressed a neuronal marker or an astrocytic marker were not significantly influenced by lithium. Moreover, lithium improved the impaired spatial learning and memory ability in Morris water maze, and U0126 attenuated the behavioral improvement by lithium. These results suggest that lithium up-regulates the generation and survival of new-born cells in the hippocampus by the ERK pathway and improves the behavioral disorder in rats after transient global cerebral ischemia.