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: Shigeki Moriguchi, Hideaki Tagashira, Yuzuru Sasaki, Jay Z Yeh, Hiroyuki Sakagami, Toshio Narahashi, Kohji Fukunaga
• Journal: Journal of neurochemistry (J Neurochem) Vol. 128 Issue 6 Pg. 927-37 (Mar 2014) ISSN: 1471-4159 [Electronic] England
• PMID: 24164423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 International Society for Neurochemistry.

Chemical References

• Cholinesterase Inhibitors
• Phenylcarbamates
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium-Calmodulin-Dependent Protein Kinase Type 4
• Camk2a protein, mouse
• Camk4 protein, mouse
• Rivastigmine

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Animals
• Animals, Outbred Strains
• CA1 Region, Hippocampal (drug effects, physiology)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 4 (genetics, metabolism)
• Cholinesterase Inhibitors (pharmacology)
• Denervation (methods)
• Disease Models, Animal
• Long-Term Potentiation (drug effects, physiology)
• Male
• Memory (drug effects, physiology)
• Memory Disorders (drug therapy, metabolism)
• Mice
• Olfactory Bulb (surgery)
• Phenylcarbamates (pharmacology)
• Rivastigmine