Why NMDA-receptor-dependent long-term potentiation may not be a mechanism of learning and memory: Reappraisal of the NMDA-receptor blockade strategy

Abstract

The hypothesis that the processes mediating the induction of long-term potentiation (LTP) in the hippocampus also subserve hippocampally mediated learning and memory has recently been examined using an NMDA-receptor antagonist (AP5) to block the induction of LTP during training on learning tasks (Morris, Anderson, Lynch, & Baudry, 1986; Staubli, Thibault, DiLorenzo, & Lynch, 1989). The authors claim that their results support the NMDA-receptor-dependent LTP/memory hypothesis. Our reappraisal of the empirical support for this claim, however, suggests that it is premature, and that some aspects of the data can be used to argue just the opposite: that NMDA-receptor-dependent synaptic changes are not critically involved in the learning and memory processes that were under investigation. We support our position by arguing that (1) these studies did not convincingly rule out sensorimotor interpretations of the behavioral impairments that were observed, and (2) in all tasks studied, the AP5-treated animals displayed substantial evidence of learning, a result that contradicts the NMDA-receptor-dependent LTP/memory hypothesis. We also consider data from studies in which the noncompetitive NMDA antagonist MK-801 was used, and we conclude that the results obtained with this agent cannot be used to support the LTP/memory hypothesis, because MK-801 does not block NMDA-receptor-dependent LTP in vivo in doses that permit animals to behave. © 1990, Psychonomic Society, Inc.. All rights reserved.