Concentration-dependent effects of protein phosphatase (PP) inhibitors implicate PP1 and PP2A in different stages of memory formation

Numerous studies have demonstrated roles for protein phosphorylation and fo r specific kinases in memory formation; however, a role for specific protei n phosphatases has not been established. Previous studies using pharmacobeh avioral methods to implicate protein phosphatase activity in memory formati on have been unable to discriminate between protein phosphatases 1 (PP1) an d 2A (PP2A), as available cell-permeable agents generally inhibit both enzy me classes. To address this difficulty the present study exploited differen ces in the potency of the selective phosphatase inhibitor, okadaic acid, to ward PP1 and PP2A. Within the context of a temporally precise animal model of memory, developed using the day-old chick (Gallus domesticus), acute adm inistration of various concentrations of okadaic acid was found to disrupt two temporally distinct stages of memory formation. When administered bilat erally into an area of the chick brain implicated in memory formation, conc entrations of okadaic acid known to selectively inhibit PP2A in vitro disru pted memory from 50 min posttraining. Higher concentrations, reported to in hibit both PP2A and PP1 in vitro, produced significant retention deficits f rom 20 min posttraining. Identical temporally specific effects were also ob tained by varying the concentration and time of administration of calyculin A, a phosphatase inhibitor with equal potency toward both enzyme classes. Hence, different phosphatase enzymes may contribute to different stages of the enzymatic cascade believed to underlie memory formation, (C) 2001 Acade mic Press.