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 + 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 Ca(2+)-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.


CONCLUSIONS
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.
Zhong
Le
L
Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai Key Laboratory of Children's Environmental Health, Shanghai, China.
Yan
Chong-Huai
CH
Lu
Cheng-Qiu
CQ
Xu
Jian
J
Huang
Hua
H
Shen
Xiao-Ming
XM
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D004777:Environment; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014268:Trifluoperazine / Q000494:pharmacology
D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein; D018492:Dopamine Antagonists; D014268:Trifluoperazine; D001973:Bromodeoxyuridine