What are the mechanisms underlying the involvement of different subtypes of NMDA receptors in inducing long-term potentiation and depression in the hippocampus?

It has been hypothesized that the sign (direction) of modification of the efficiency of synaptic transmission depends on the subtype of N-methyl-D-aspartate (NMDA)-sensitive receptors involved. Activation of NMDA receptors with 2A subunits facilitates the induction of long-term potentiation, while receptors with 2B subunits facilitate the induction of long-term depression. However, experimental data have been obtained which contradict this hypothesis. We suggest an alternative hypothesis to explain currently available data. According to this hypothesis, activation of NMDA receptors containing different subunits can lead both to long-term potentiation and long-term depression, depending on the post-tetanic increase in the postsynaptic Ca(2+) concentration relative to the increase induced by preceding stimulation. Activation of NMDA receptors containing 2B subunits can lead to long-term depression of the excitatory input to pyramidal neurons because of the presence of these receptors on inhibitory interneurons, with induction of long-term potentiation on the interneuron and potentiation of inhibitory transmission between interneurons and pyramidal cells.