Functional relationship between NMDA receptor-mediated synaptic current duration and Hebbian learning

N-methyl-D-Aspartate (NMDA) receptor-mediated Hebbian learning is related to NMDA excitatory postsynaptic current (epsc) duration via calcium-threshold for the induction of long-term potentiation (LTP). Decreasing epsc duration decreases total calcium influx and hence makes it harder to elicit LTP. This model explains developmental decrease in susceptibility to LTP with decreases in epsc duration, and genetic enhancement of learning by overexpressing NR2B, which increased epsc duration. However there are additional data that do not fit in this threshold model. NR2A knockout mice have reduced LTP and learning in spite of the fact that the lack of NR2A subunit increases epsc decay time. Furthermore, aged dementia patients undergoing treatment with memantine, which decreases NMDA epsc duration, showed improvement in learning and memory.

In an effort to resolve these inconsistencies, we formulated a model of NMDA receptor-mediated temporal correlation learning. Assuming temporal coincidence of epscs is the physiological basis of associative learning we obtained an expression for learning in terms of NMDA epsc duration. We find that learning is an inverted-U function of NMDA epsc duration. Optimal epsc duration is ~250 msec, which gives maximal LTP of 200%.