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

TLDR

A preliminary report of parts of this work has been published (Morris et al., 1986a). The study reports five experiments investigating the role of NMDA receptors in specific learning types. The authors infused AP5 intraventricularly at a dose that blocks hippocampal LTP in vivo while sparing normal synaptic transmission, and tested whether sensorimotor disturbances could account for the learning deficits. Chronic AP5 infusion selectively impaired spatial but not visual discrimination learning, did not affect retention of spatial information, and was independent of sensorimotor disturbances, supporting a role for NMDA receptors in spatial learning and linking LTP saturation to anterograde spatial amnesia.

Abstract

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).