Nuclear calcium/calmodulin regulates memory consolidation.
The neuronal response to a Ca2+ stimulus is a complex process involving direct Ca2+/calmodulin (CaM) actions as well as secondary activation of multiple signaling pathways such as cAMP and ERK (extracellular signal-regulated kinase). These signals can act in both the cytoplasm and the nucleus to control gene expression. To dissect the role of nuclear from cytoplasmic Ca2+/CaM signaling in memory formation, we generated transgenic mice that express a dominant inhibitor of Ca2+/CaM selectively in the nuclei of forebrain neurons and only after the animals reach adulthood. These mice showed diminished neuronal activity-induced phosphorylation of cAMP response element-binding protein, reduced expression of activity-induced genes, altered maximum levels of hippocampal long-term potentiation, and severely impaired formation of long-term, but not short-term, memory. Our results demonstrate that nuclear Ca2+/CaM signaling plays a critical role in memory consolidation in the mouse.
Limbäck-Stokin
Klara
K
Institute for Childhood and Neglected Diseases and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Korzus
Edward
E
Nagaoka-Yasuda
Rie
R
Mayford
Mark
M
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002147:Calmodulin / Q000502:physiology*; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000502:physiology; D003216:Conditioning, Operant; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D005106:Exploratory Behavior; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D005786:Gene Expression Regulation; D016762:Genes, fos; D006624:Hippocampus / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D021641:Recognition, Psychology / Q000502:physiology; D012640:Seizures / Q000378:metabolism
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004318:Doxycycline; D002118:Calcium