CaMKII activity is essential for improvement of memory-related behaviors by chronic rivastigmine treatment

Shigeki Moriguchi, Hideaki Tagashira, Yuzuru Sasaki, Jay Z. Yeh, Hiroyuki Sakagami, Toshio Narahashi, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)927-937
Number of pages11
JournalJournal of Neurochemistry
Issue number6
Publication statusPublished - 2014 Mar


  • Alzheimer's disease
  • CaMKII
  • long-term potentiation
  • OBX mice
  • rivastigmine


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