title: CaMKII activity is essential for improvement of memory-related behaviors by chronic rivastigmine treatment.
abstract: Because the cholinergic system is down-regulated in the brain of Alzheimer's disease patients, cognitive deficits in Alzheimer's disease patients are significantly improved by rivastigmine treatment. To address the mechanism underlying rivastigmine-induced memory improvements, we chronically treated olfactory bulbectomized (OBX) mice with rivastigmine. The chronic rivastigmine treatments for 12-13 days starting at 10 days after OBX operation significantly improved memory-related behaviors assessed by Y-maze task, novel object recognition task, passive avoidance task, and Barnes maze task, whereas the single rivastigmine treatment failed to improve the memory. Consistent with the improved memory-related behaviors, long-term potentiation in the hippocampal CA1 region was markedly restored by rivastigmine treatments. In immunoblotting analyses, the reductions of calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in the CA1 region in OBX mice were significantly restored by rivastigmine treatments. In addition, phosphorylation of AMPAR subunit glutamate receptor 1 (GluA1) (Ser-831) and cAMP-responsive element-binding protein (Ser-133) as downstream targets of CaMKII and CaMKIV, respectively, in the CA1 region was also significantly restored by chronic rivastigmine treatments. Finally, we confirmed that rivastigmine-induced improvements of memory-related behaviors and long-term potentiation were not obtained in CaMKIIα(+/-) mice. On the other hand, CaMKIV(-/-) mice did not exhibit the cognitive impairments. Taken together, the stimulation of CaMKII activity in the hippocampus is essential for rivastigmine-induced memory improvement in OBX mice.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Moriguchi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Jay Z
authors.initials: JZ
authors.lastname: Yeh
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakagami
authors.forename: Toshio
authors.initials: T
authors.lastname: Narahashi
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D021461:Animals, Outbred Strains; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000235:genetics / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003714:Denervation / Q000379:methods; D004195:Disease Models, Animal; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D009830:Olfactory Bulb / Q000601:surgery; D048448:Phenylcarbamates / Q000494:pharmacology*; D000068836:Rivastigmine
chemical_list: D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517671:Camk2a protein, mouse; C517685:Camk4 protein, mouse; D000068836:Rivastigmine
keywords: Alzheimer's disease; CaMKII; OBX mice; long-term potentiation; rivastigmine