Calmodulin activation is required for the enhancement of hippocampal neurogenesis following environmental enrichment

Objective: An enriched environmental exposure has been shown to promote hippocampal neurogenesis, which is an important mechanism underlying enrichment-induced memory improvement. The cAMP response element-binding protein is an important stimulus-inducible factor in the brain and is crucial for neurogenesis and memory ability. Calmodulin activation is important for activity-induced cAMP response element-binding protein phosphorylation. The aim of this study was to explore the effects of calmodulin activation on hippocampal neurogenesis and spatial memory improvement in rats exposed to enriched environment. Methods: Ninety-six neonatal pups were assigned to four groups: control group, enriched environment group, control a+ trifluoperazine (trifluoperazine, 5 mg/kg) group and enriched environment + trifluoperazine group. Pups in the enriched environment and enriched environment + trifluoperazine groups were exposed to enriched environments for 25 min from P10 to P24. Half of pups in each group were intraperitoneally injected with 50 mg/kg BrdU every other day from P10 to P24. Pups without BrdU injection were euthanized at P24, and hippocampal nuclear Ca2+-calmodulin and phosphorylated cAMP response element-binding protein were detected. Morris water maze acquisition and subsequent probe trial retention were performed in remained rats after P50 and immunohistochemistry was used to identify proliferating cells in the dentate gyrus 1 day after the probe trial. Results: The trifluoperazine injection could completely inhibit the environmental enrichment-induced activations of calmodulin and cAMP response element-binding protein. Enriched environmental exposure could improve Morris water maze performance and increase hippocampal BrdU-labeled cells, but the effects could be completely blocked by trifluoperazine injection. Conclusion: This study proves that the activation of calmodulin is essential for an enriched environmental exposure-induced cAMP response element-binding protein activation, hippocampal neurogenesis and spatial memory improvement. [Neurol Res 2009; 31: 707-713]