Kinase Activity Critical to Memory Formation

A team of Japanese neuroscientists has used advanced genetic engineering techniques to create a line of mice lacking the kinase activity in a memory-related enzyme called Ca2+/calmodulin-dependent protein kinase II-alpha (CaMKII-alpha).

CaMKII-alpha belongs to the family of multifunctional CaM kinases that are capable of carrying out several different catalytic functions. They play a role in many neural processes, such as neurotransmitter secretion, transcription factor regulation, and glycogen metabolism. Between 1% and 2% of the proteins in the brain are CaM kinase II, with CaMKII-alpha being enriched in the hippocampus, the memory center of the brain. CaMKII-alpha is thought to be an essential mediator of activity-dependent synaptic plasticity and memory functions.

To study how CaMKII-alpha influences the memory process, investigators from the Japanese National Institute for Physiological Sciences (Okazaki, Japan) genetically engineered a line of mice that contained a mutant CaMKII-alpha gene. The K42R mutation caused the animals to produce CaMKII-alpha that did not have kinase activity.

Results of experiments conducted with the K42R mutant mice were published in the June 10, 2009, issue of the Journal of Neuroscience. The animals were found to produce the normal amount of CaMKII-alpha but to display as little kinase activity as a line of mice that completely lacked the CaMKII-alpha gene. The K42R mice showed a severe impairment in inhibitory avoidance learning, a form of memory that is dependent on the hippocampus.

"We demonstrated that the mutant mouse has a severe memory deficit because of the lack of the kinase activity of CaMKII-alpha. This finding supports the idea that the kinase activity of CaMKII-alpha is essential to memory functions. Such a memory-deficit mutant mouse could serve as an animal model to study the molecular mechanisms of memory, and be a useful tool for the development and screening of therapeutic reagents for memory-deficit disorders. It may also help open a new therapeutic approach to memory dysfunctions in patients,” said first author Dr. Yoko Yamagata, a researcher at the National Institute for Physiological Sciences.

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National Institute for Physiological Sciences