Cyclosporin A, FK506 and rapamycin produce multiple, temporally distinct, effects on memory following single-trial, passive avoidance training in the chick.

Few studies have used a pharmaco-behavioural methodology to directly investigate roles for the calcium-dependent protein phosphatase calcineurin (CaN) in memory formation, due partly to the absence of specific inhibitory agents. A number of drugs with different inhibitory profiles were used to examine this issue in groups of chicks trained on a single-trial, passive-avoidance task. Bilateral intracranial administration of the immunosuppressants FK506 and cyclosporin A (CyA) led to two temporally distinct effects, distinguished by the concentration of drug required and the effective time of administration relative to training. In addition to inhibiting CaN, CyA and FK506 inhibit distinct classes of peptidyl prolyl-cis/trans-isomerases (PPIases). Other agents known to inhibit these enzymes, including the Map kinase inhibitor Rapamycin, also induced memory deficits in a complex, dose- and time-of-administration-dependent, manner. The data fail to conclusively implicate CaN in memory formation, but are consistent with proposals that a phosphatase cascade may participate in an early stage of information storage. PPIases may be required at a later stage to catalyse the folding of new or translocated proteins, the synthesis of which is required for formation of long-term memory, although other possible explanations for the data remain to be investigated.