Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5.

This paper reports a series of 5 experiments concerned with a possible role for N-methyl-D-aspartate (NMDA) receptors in certain types of learning. The results show that chronic intraventricular infusion of the NMDA receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (D,L-AP5) caused an impairment of spatial but not of visual discrimination learning in rats. Such selectivity of the learning impairment occurred despite widespread distribution of the drug throughout the CNS. AP5 sometimes caused a disturbance of sensorimotor function during learning, but one experiment addressing whether this disturbance could be responsible for the spatial learning impairment established that it was statistically independent. Another experiment showed that AP5 did not affect the retention of previously acquired spatial information. These behavioral effects were all obtained with a concentration of AP5 that, in a final study, was found to be sufficient to block hippocampal long-term potentiation (LTP) in vivo without affecting normal synaptic transmission. Taken together, these observations (1) implicate NMDA receptors in certain types of learning, and (2) extend recent work showing that saturation of LTP causes an anterograde spatial amnesia (McNaughton et al., 1986). A preliminary report of parts of this work has been published (Morris et al., 1986a).