As far as memory is concerned, most people's primary worry is that theirs seems to be going, or will go one day. But even with memories, there can be too much of a good thing. "A component of intelligence involves the flexibility to relearn" as things change, James Bibb told BioWorld Today.

When such flexibility is lacking, people can become prisoners of memories they would be better off forgetting. Bibb named drug addiction, where learned associations can lead to cravings; depression, which has "a learned component of despair;" and post-traumatic stress disorder, in which "the brain reconsolidates traumatic memories to the point where it becomes difficult for the individual to function."

Bibb is an assistant professor at the University of Texas Southwestern Medical Center in Dallas and the senior author of a paper now available online in Nature Neuroscience that describes how he and his colleagues from the University of Texas, Rockefeller University, and the Centre Universitaire in Strasbourg, France, were able to boost the brain's flexibility by blocking a kinase known as cdk5.

The authors wrote that cdk5 has been implicated in "a plethora of normal and pathological processes in the mammalian CNS," and Bibb described the current interest in the kinase as "logarithmic," with each month bringing more papers than the last. But much of that interest has been recent, in part because the kinase has been hard to study. Pharmacological inhibitors tend to be unspecific, and knocking it out is lethal during embryonic development.

Bibb and his team were able to make an inducible cdk5 knockout, which led to a reduction of cdk5 levels by 50 percent to 70 percent in most of the brain, and close to 90 percent in the hippocampus, which is an important structure for certain, relatively complex types of learning.

Compared to controls, those mice performed better on several learning tasks that involve the hippocampus. The mice also were more flexible in their learning. When a situation, such as a maze route, changed, the engineered mice were faster than wild-types to realize that a new game was being played, and work out a new solution.

On a cellular level, the researchers found that the reduction in cdk5 levels appeared to affect a type of receptor known as NMDA receptors, which are important for learning and memory consolidation. NMDA receptors are made up of several subunits, and depending on their subunit composition, can be more or less responsive to the relationships between several stimuli. Bibb said it appears that mice lacking cdk5 have more NMDA receptors that are involved with new learning, as opposed to with memory consolidation, which might explain the increased flexibility they show.

Interestingly, though the most obvious guess as to a kinase's mechanism of action would be that it phosphorylates something, that is not what Bibb and his team found. Instead, cdk5 appears to have more of a structural role, forming a complex with several proteins that allows another enzyme to cleave the NMDA receptors.

Targeting cdk5 could be helpful in increasing brain flexibility, but the kinase also has been implicated in neurodegeneration and Alzheimer's disease, and tweaking it potentially could be useful for a variety of disorders. Bibb described himself as being in discussions with several pharmaceutical and biotechnology companies, but from his perspective, the more, the merrier. "We're looking for additional partnerships as we move from transgenic to more pharmacological approaches," he said.

No Comments