アブカムでは最適な動作のために Google Chrome など最新ブラウザでの閲覧を推奨します。
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.
1. Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).
2. Bliss, T. V. & Collingridge, G. L. Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol Brain 6, 5 (2013).
3. Volianskis, A. et al. Long-term potentiation and the role of N-methyl-D-aspartate receptors. Brain Res 1621, 5–16 (2015).
4. Collingridge, G. L. et al. The NMDA receptor as a target for cognitive enhancement. Neuropharmacology 64, 13–26 (2013).
5. Berretta, N. & Jones, R. S. Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex. Neuroscience 75, 339–344 (1996).
6. McGuinness, L. et al. Presynaptic NMDARs in the hippocampus facilitate transmitter release at theta frequency. Neuron 68, 1109–1127 (2010).
7. Bliss, T. V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol (Lond) 232, 331–356 (1973).
8. Dudek, S. M. & Bear, M. F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci USA 89, 4363–4367 (1992).
9. Collingridge, G. L., Kehl, S. J. & McLennan, H. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol (Lond) 334, 33–46 (1983).
10. Davies, J., Francis, A. A., Jones, A. W. & Watkins, J. C. 2-Amino-5-phosphonovalerate (2APV), a potent and selective antagonist of amino acid-induced and synaptic excitation. Neurosci Lett 21, 77–81 (1981).
11. Davies, J. & Watkins, J. C. Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord. Brain Res 235, 378–386 (1982).
12. Hrabetova, S. et al. Distinct NMDA receptor subpopulations contribute to long-term potentiation and long-term depression induction. J Neurosci 20, RC81 (2000).
13. Liu, L. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021–1024 (2004).
14. Massey, P. V. et al. Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci 24, 7821–7828 (2004).
15. Berberich, S. et al. Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation. Journal of Neuroscience 25, 6907–6910 (2005).
16. Weitlauf, C. et al. Activation of NR2A-containing NMDA receptors is not obligatory for NMDA receptor-dependent long-term potentiation. J Neurosci 25, 8386–8390 (2005).
17. Bartlett, T. E. et al. Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. Neuropharmacology 52, 60–70 (2007).
18. Li, R., Huang, F.-S., Abbas, A.-K. & Wigström, H. Role of NMDA receptor subtypes in different forms of NMDA-dependent synaptic plasticity. BMC Neurosci 8, 55 (2007).
19. Berberich, S., Jensen, V., Hvalby, O., Seeburg, P. H. & Köhr, G. The role of NMDAR subtypes and charge transfer during hippocampal LTP induction. Neuropharmacology 52, 77–86 (2007).
20. Park, P. et al. NMDA receptor-dependent long-term potentiation comprises a family of temporally overlapping forms of synaptic plasticity that are induced by different patterns of stimulation. Philos Trans R Soc Lond, B, Biol Sci 369, 20130131–20130131 (2014).
21. Volianskis, A. & Jensen, M. S. Transient and sustained types of long-term potentiation in the CA1 area of the rat hippocampus. J Physiol (Lond) 550, 459–492 (2003).
22. Volianskis, A. et al. Different NMDA receptor subtypes mediate induction of long-term potentiation and two forms of short-term potentiation at CA1 synapses in rat hippocampus in vitro. J Physiol (Lond) 591, 955–972 (2013).
23. Volianskis, A., Collingridge, G. L. & Jensen, M. S. The roles of STP and LTP in synaptic encoding. PeerJ 1, e3 (2013).