Role of calcineurin in inhibiting disadvantageous associations

Calcineurin is an important calcium-dependent phosphatase that is evolutionarily conserved in all studied species, and has been implicated in the consolidation and maintenance of new memories. However, recent evidence has extended the role of calcineurin. In contrast to learning tasks that require behavioral acquisition, extinction tasks that require behavioral inhibition have been shown to be reliant on calcineurin. In the present study, using a Morris water maze, we have demonstrated that pharmacological inhibition of calcineurin causes augmentation of spatial learning and perseveration of spatial reversal-learning in a dose-dependent manner. Direct infusions of a specific calcineurin inhibitor, cyclosporine A, into the dorsal hippocampi bilaterally, prior to spatial learning, led to increased learning, whereas similar injections of cyclosporine A following a spatial learning task and prior to a spatial reversal-learning task resulted in perseveration of reversal-learning. Our results indicate that injections of cyclosporin A resulted in decreased calcineurin activity in the dorsal hippocampus and increased difficulty in switching to new task demands, in a dose-dependent manner, despite evidence indicating no deficit in ability to learn new information. Therefore, calcineurin activity contributes to the inhibition of previously learned but unwanted behavioral responses during competitive spatial learning. Involvement of calcineurin in extinction of fear memory has recently been demonstrated. Our results also indicate that calcineurin activity plays a role in memory extinction in spatial memory tasks, and therefore, suggest that calcineurin might be an important molecule in mediating behavioral flexibility in general.