The subunit composition of NMDA receptors might be the determining factor in the direction of hippocampal plasticity.
Although the importance of NMDA (N-methyl-D-aspartate) receptors for long-term plasticity at many synapses is well established, it is unclear how activation of these receptors can lead to either potentiation or depression of synaptic activity under different circumstances. Now, Liu and colleagues suggest that the subunit composition of the receptors might be the determining factor in the direction of plasticity.
At synapses in hippocampal area CA1, specific patterns of activation can lead to long-term potentiation (LTP) or long-term depression (LTD), both of which depend on the activation of NMDA receptors. High-frequency stimulation produces LTP, whereas low-frequency stimulation leads to LTD. Partially blocking NMDA synapses with an antagonist, APV (D,L-2-amino-5-phosphophonovaleric acid), blocks the induction of LTP but not that of LTD, and this finding led to the idea that the direction of plasticity depends on the degree of activation of the NMDA receptors and therefore the level and kinetics of NMDA receptor-gated Ca2+ influx. But Liu et al. have come up with a different explanation.
NMDA receptors consist of NR1 and NR2 subunits. There are four types of NR2 subunit, with the primary ones in the CA1 region of the hippocampus being NR2A and NR2B. When the authors used an NR2B-specific antagonist, such as ifenprodil, they were unable to induce LTD, even though LTP was unaffected. Conversely, an NR2A-specific blocker, NVP-AAM077, prevented the induction of LTP but had little effect on LTD. These results support a new model, in which differential activation of NMDA receptors containing either the NR2A or the NR2B subunit controls whether synaptic activity is potentiated or depressed.
If this is the case, a low dose of APV that only partially blocked NMDA receptor activation would be expected to prevent LTP but not LTD, because NR2A-containing receptors are more sensitive to APV than those that contain NR2B. The idea is also consistent with previous findings, such as the fact that the NR2A/NR2B ratio increases during development, and LTD is more difficult to induce in more mature animals. However, there are also some problems for the theory. For example, a previous study by Tang et al. found that overexpression of NR2B subunits in the forebrain of mice increased levels of LTP, not LTD. Furthermore, different rules might apply in different parts of the brain.
Further work will no doubt help to clarify such issues, and should establish how different stimulation protocols might preferentially activate receptors that contain different types of subunit. It should also investigate what might happen downstream of receptor activation: there is already evidence that NR2A-containing receptors might couple to different signalling pathways from NR2B-containing receptors, and this provides a potential mechanism for their different effects on long-term plasticity.
Rachel Jones
References
Liu, L. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science304, 1021–1024 (2004) | Article | PubMed |
Tang, Y. P. et al. Genetic enhancement of learning and memory in mice. Nature401, 63–69 (1999) | Article | PubMed |
