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N-methyl-d-aspartate receptors (NMDARs) are thought to be centrally involved in normal brain function, supporting synaptic transmission and learning and memory1-3, and their dysfunction is implicated in many pathophysiological processes4. It is the triple gating of the NMDA receptor, requiring co-activation by glutamate and glycine together with the voltage dependent relief of the Mg2+ block, that makes NMDARs particularly suited to regulate synaptic plasticity. When situated post-synaptically NMDARs can sense the incidence of pre-synaptic neurotransmitter release that has to be synchronized with significant depolarizing post-synaptic activation in order to result in channel opening and Ca2+ influx into the intracellular compartment. Thus, NMDARs act as coincidence detectors of pre- and post-synaptic activity, endowing synapses with “Hebbian like” plasticity1 or function as autoreceptors controlling release of glutamate at presynaptic sites5,6. The strength of the compartmentalized Ca2+ signal and its duration are thought to underlie activation of a number of intracellular second messengers that can either up-regulate or down-regulate the strength of synaptic transmission leading to induction of long-term potentiation (LTP7) and long-term depression (LTD8), respectively. Although there are NMDA receptor independent forms of LTP and LTD that can be triggered by other receptor systems, it is the NMDA receptor dependent types that have attracted most research interest3.
NMDA-receptor dependency of LTP9 and LTD8 was demonstrated first in hippocampal slices using D-AP5, an antagonist that is selective for NMDARs against other types of glutamate receptors10,11. Further work, involving compounds that display preference to specific subtypes of GluN2 subunits, showed that LTP and LTD might be induced through receptors expressing different NMDAR subtypes12,13 suggesting that GluN2A containing receptors are involved in the induction of LTP whereas GluN2B containing NMDARs are important in the induction of LTD13. Notably, induction of LTD was shown to be dependent on activation of extrasynaptic NMDA receptors containing GluN2B subunits14. Subsequent work disputed such straightforward segregation of involvement of separate subunits in the induction of LTP and LTD15-19.
In addition to the research concerning LTP and LTD, which was performed primarily on tissues from juvenile animals, research in adults showed that the process of LTP reflects a number of temporally overlapping phases of potentiation20. Thus, induction of an early phase, which precedes LTP and is frequently termed short-term potentiation (STP or transient LTP, t-LTP21), has been shown to depend on activation of NMDARs comprised of GluN2B and GluN2D subunits3,22. In contrast to STP, triheteromeric NMDARs containing both GluN2A and GluN2B subunits were found to be involved in the induction of LTP3,22 and it was shown that STP and LTP can subserve different synaptic functions during encoding and transfer of information23. Thus, NMDA receptor mediated synaptic plasticity appears more complex than hitherto imagined and future research developments will be dependent on availability of new pharmacological tools with improved efficacy and better subunit selectivity.
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