The select action of hippocampal calcium calmodulin protein kinase II in mediating exercise-enhanced cognitive function.

We found that a single week of exercise enhanced cognitive function on the Morris water maze (MWM), such that exercise animals were significantly better than sedentary controls at learning and recalling the location of the platform. In order to elucidate the role that calcium calmodulin protein kinase II (CAMKII) holds in mediating the exercise-induced enhancement in learning and memory, a specific antagonist of CAMKII, KN-62, was used to block CAMKII in the rat hippocampus during a 1-week voluntary exercise period. Following, a two-trial-per-day MWM was performed for five consecutive days, succeeded by a probe trial 2 days later. Inhibiting CAMKII action during exercise blocked the ability of exercise to enhance memory retention on the MWM; the recall abilities of exercise animals receiving the CAMKII blocker were significantly worse than those of both sedentary and exercise controls. Conversely, CAMKII may not play a significant role in mediating the effects of exercise on learning acquisition as inhibiting CAMKII failed to block the exercise-induced enhancement in learning acquisition. Our results also show that CAMKII activation early during MWM learning may be counterproductive to learning acquisition, as exercising animals given the CAMKII inhibitor performed significantly (P<0.001) better than exercising control animals and sedentary controls only on day 2 of the MWM. Inhibiting CAMKII also blocked the exercise-induced upregulation of molecules critical for learning and memory, brain-derived neurotrophic factor (BDNF) and the transcription activator cAMP response-element-binding protein, which is regulated by and downstream to BDNF action. These findings indicate that hippocampal CAMKII may have a refined role in mediating the effects of exercise on cognition, selectively functioning to regulate memory retention.