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The NMDA receptor 30 years on
NP5068_proof ■ 8 May 2013 ■ 1/2
Neuropharmacology xxx (2013) 1–2
Contents lists available at SciVerse ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
Foreword
The NMDA receptor 30 years on This issue of Neuropharmacology celebrates the thirtieth anniversary of the publication of Collingridge, Kehl and McLennan’s seminal 1983 study demonstrating that the NMDA receptor controls the induction of long-term potentiation (LTP) in area CA1 of the hippocampus (Collingridge et al., 1983). The NMDA receptor has become so embedded in our thinking about synaptic plasticity that it is difficult now to imagine LTP in a landscape devoid of the NMDA receptor. But in the decade following the publication of the first full descriptions of LTP (Bliss and Lømo, 1973; Bliss and Gardner-Medwin, 1973), it had not yet been established beyond doubt that glutamate was the transmitter at hippocampal excitatory synapses. Indeed, as late as 1985, Graham Collingridge was hedging his bets, writing that ‘hippocampal synapses that display LTP probably utilize amino acids such as L-aspartate and L-glutamate as their transmitters’ (Collingridge, 1985). Glutamate receptors were at that time split into two classes depending on whether they were excited by the selective agonists quisqualate/kainate (Q/K) or N-methyl-D-aspartate. No highly selective antagonist was available for Q/K glutamate receptors, but in 1981 Jeff Watkins and his colleagues in Bristol had synthesised a potent and selective antagonist of the NMDA receptor (Davies et al., 1981). This was D-2-amino-5-phosphonovalerate (APV or AP5), and Graham Collingridge, who as an undergraduate at Bristol had got to know Watkins well, took it with him to Vancouver when he joined Hugh MacLennan’s lab as a postdoc in 1980. The famous result, that APV blocks the induction of LTP but has no effect on baseline transmission, was not flagged up in the title of the 1983 paper in Journal of Physiology, and I remember the jolt of surprise and delight on first coming across Fig. 5. In fact, dramatic as the finding was, it took another couple of years before its full significance became apparent. It is instructive to summarise the rudimentary state of knowledge regarding LTP induction rules at the time the 1983 paper was published. Two earlier papers from Graham Goddard’s laboratory at Dalhousie University had pointed to a postsynaptic ‘locus of control’ for induction. First, in the perforant path a cooperativity rule operated; only strong stimuli, activating a sufficiently large number of fibres, induced LTP (Bliss and Gardner-Medwin, 1973; McNaughton et al., 1978); secondly, commissural stimulation that resulted in strong inhibition of granule cells blocked the induction of LTP at perforant path – granule cell synapses (Douglas et al., 1982). These results suggested the following induction rule for LTP: A synapse will be potentiated if and only if it is active at a time when the dendrite on which it is located is strongly depolarised. Later in 1983 came compelling evidence that the postsynaptic cell played an essential role in generating LTP, when Gary Lynch’s
0028-3908/$ – see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.neuropharm.2013.04.049
56 57 58 59 60 lab showed that LTP could not be obtained in cells injected with 61 the calcium chelator EGTA (Lynch et al., 1983). This was followed 62 in 1984 by incisive insights into the mechanism underlying the 63 voltage-dependence of the NMDA receptor. The low conductance 64 of the receptor at resting potential was shown to be due to a block 65 of the receptor channel by Mg2þ ions, a block that was relieved by 66 depolarization (Nowak et al., 1984). Finally, also in 1984, MacDermott et al. (1986) showed that calcium ions permeated Q2 67 68 the open NMDA channel. All was now in place for the new synthe69 sis, promulgated independently by Collingridge (1985) and by 70 Wigström and Gustafsson (1985). The induction rule was entirely 71 explained by the voltage-dependent properties of the NMDA recep72 tor and could now be rewritten as ‘a synapse will be potentiated 73 whenever the conditions that allow the NMDA channel to open 74 are satisfied’; moreover, the events leading to the initial increase 75 in synaptic strength were triggered by permeation of Ca2þ through 76 the activated NMDA receptor channel. Three properties of LTP – 77 cooperativity, input specificity and associativity – were at a stroke 78 explained by the peculiar properties of this singular protein. The 79 fact that two events had to be satisfied to activate the receptor, 80 release of transmitter and a sufficient depolarization of the post81 synaptic membrane, sealed the status of the NMDA receptor as a 82 molecular coincidence detector, or AND gate. The papers that 83 follow in this Special Issue of Neuropharmacology bear witness to 84 the fact that the exceptional elegance of this molecular account of 85 the induction of NMDA receptor-dependent LTP remains a powerful 86 stimulus thirty years later. 87 88 89 References 90 Bliss, T.V.P., Lømo, T., 1973. Long-lasting potentiation in the dentate gyrus of the 91 anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 92 232, 331–356. 93 Bliss, T.V.P., Gardner-Medwin, A.R., 1973. Long-lasting potentiation in the dentate gyrus of the unanaesthetized rabbit following stimulation of the perforant 94 path. J. Physiol. 232, 357–374. 95 Collingridge, G.L., 1985. Long term potentiation in the hippocampus: mecha96 nisms of initiation and modulation by neurotransmitters. Trends Pharm. Sci. 6, 407–411. 97 Collingridge, G.L., Kehl, S.J., McLennan, H., 1983. Excitatory amino acids in synaptic 98 transmission in the Schaffer collateral-commissural pathway of the rat hippo99 campus. J. Physiol. 334, 33–46. 100 Davies, J., Francis, A.A., Jones, A.W., Watkins, J.C., 1981. 2-Amino-5-phosphonovalerate (2APV), a potent and selective antagonist of amino acid-induced and synap101 tic excitation. Neurosci. Lett. 21, 77–81. 102 Douglas, R.M., Goddard, G.V., Riives, M., 1982. Inhibitory modulation of long-term 103 potentiation: evidence for a postsynaptic locus of control. Brain Res. 240, 259–272. 104 Lynch, G., Larson, J., Kelso, S., Barrionuevo, G., Schottler, F., 1983. Intracellular injec105 tions of EGTA block induction of hippocampal long-term potentiation. Nature 106 305, 719–721. 107 108 109 110
Please cite this article in press as: Bliss, T., The NMDA receptor 30 years on, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.04.049
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2
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Foreword / Neuropharmacology xxx (2013) 1–2
MacDermott, A.B., Mayer, M.L., Westbrook, G.L., Smith, S.J., Barker, J.L., 1986. NMDAreceptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321, 519–522. McNaughton, B.L., Douglas, R.M., Goddard, G.V., 1978. Synaptic enhancement in fascia dentate: cooperativity among coactive afferents. Brain Res. 157, 277–293. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A., Prochiantz, A., 1984. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465.
Wigström, H., Gustafsson, B., 1985. On long-lasting potentiation in the hippocampus: a proposed mechanism for its dependence on coincident pre- and postsynaptic activity. Acta Physiol. Scand. 123, 519–522.
Tim Bliss Q3 Division of Neurophysiology, National Institute for Medical Research, UK Q1
Please cite this article in press as: Bliss, T., The NMDA receptor 30 years on, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.04.049
118 119 120 121 122 123 124
Neuropharmacology xxx (2013) 1–2
Contents lists available at SciVerse ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
Foreword
The NMDA receptor 30 years on This issue of Neuropharmacology celebrates the thirtieth anniversary of the publication of Collingridge, Kehl and McLennan’s seminal 1983 study demonstrating that the NMDA receptor controls the induction of long-term potentiation (LTP) in area CA1 of the hippocampus (Collingridge et al., 1983). The NMDA receptor has become so embedded in our thinking about synaptic plasticity that it is difficult now to imagine LTP in a landscape devoid of the NMDA receptor. But in the decade following the publication of the first full descriptions of LTP (Bliss and Lømo, 1973; Bliss and Gardner-Medwin, 1973), it had not yet been established beyond doubt that glutamate was the transmitter at hippocampal excitatory synapses. Indeed, as late as 1985, Graham Collingridge was hedging his bets, writing that ‘hippocampal synapses that display LTP probably utilize amino acids such as L-aspartate and L-glutamate as their transmitters’ (Collingridge, 1985). Glutamate receptors were at that time split into two classes depending on whether they were excited by the selective agonists quisqualate/kainate (Q/K) or N-methyl-D-aspartate. No highly selective antagonist was available for Q/K glutamate receptors, but in 1981 Jeff Watkins and his colleagues in Bristol had synthesised a potent and selective antagonist of the NMDA receptor (Davies et al., 1981). This was D-2-amino-5-phosphonovalerate (APV or AP5), and Graham Collingridge, who as an undergraduate at Bristol had got to know Watkins well, took it with him to Vancouver when he joined Hugh MacLennan’s lab as a postdoc in 1980. The famous result, that APV blocks the induction of LTP but has no effect on baseline transmission, was not flagged up in the title of the 1983 paper in Journal of Physiology, and I remember the jolt of surprise and delight on first coming across Fig. 5. In fact, dramatic as the finding was, it took another couple of years before its full significance became apparent. It is instructive to summarise the rudimentary state of knowledge regarding LTP induction rules at the time the 1983 paper was published. Two earlier papers from Graham Goddard’s laboratory at Dalhousie University had pointed to a postsynaptic ‘locus of control’ for induction. First, in the perforant path a cooperativity rule operated; only strong stimuli, activating a sufficiently large number of fibres, induced LTP (Bliss and Gardner-Medwin, 1973; McNaughton et al., 1978); secondly, commissural stimulation that resulted in strong inhibition of granule cells blocked the induction of LTP at perforant path – granule cell synapses (Douglas et al., 1982). These results suggested the following induction rule for LTP: A synapse will be potentiated if and only if it is active at a time when the dendrite on which it is located is strongly depolarised. Later in 1983 came compelling evidence that the postsynaptic cell played an essential role in generating LTP, when Gary Lynch’s
0028-3908/$ – see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.neuropharm.2013.04.049
56 57 58 59 60 lab showed that LTP could not be obtained in cells injected with 61 the calcium chelator EGTA (Lynch et al., 1983). This was followed 62 in 1984 by incisive insights into the mechanism underlying the 63 voltage-dependence of the NMDA receptor. The low conductance 64 of the receptor at resting potential was shown to be due to a block 65 of the receptor channel by Mg2þ ions, a block that was relieved by 66 depolarization (Nowak et al., 1984). Finally, also in 1984, MacDermott et al. (1986) showed that calcium ions permeated Q2 67 68 the open NMDA channel. All was now in place for the new synthe69 sis, promulgated independently by Collingridge (1985) and by 70 Wigström and Gustafsson (1985). The induction rule was entirely 71 explained by the voltage-dependent properties of the NMDA recep72 tor and could now be rewritten as ‘a synapse will be potentiated 73 whenever the conditions that allow the NMDA channel to open 74 are satisfied’; moreover, the events leading to the initial increase 75 in synaptic strength were triggered by permeation of Ca2þ through 76 the activated NMDA receptor channel. Three properties of LTP – 77 cooperativity, input specificity and associativity – were at a stroke 78 explained by the peculiar properties of this singular protein. The 79 fact that two events had to be satisfied to activate the receptor, 80 release of transmitter and a sufficient depolarization of the post81 synaptic membrane, sealed the status of the NMDA receptor as a 82 molecular coincidence detector, or AND gate. The papers that 83 follow in this Special Issue of Neuropharmacology bear witness to 84 the fact that the exceptional elegance of this molecular account of 85 the induction of NMDA receptor-dependent LTP remains a powerful 86 stimulus thirty years later. 87 88 89 References 90 Bliss, T.V.P., Lømo, T., 1973. Long-lasting potentiation in the dentate gyrus of the 91 anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 92 232, 331–356. 93 Bliss, T.V.P., Gardner-Medwin, A.R., 1973. Long-lasting potentiation in the dentate gyrus of the unanaesthetized rabbit following stimulation of the perforant 94 path. J. Physiol. 232, 357–374. 95 Collingridge, G.L., 1985. Long term potentiation in the hippocampus: mecha96 nisms of initiation and modulation by neurotransmitters. Trends Pharm. Sci. 6, 407–411. 97 Collingridge, G.L., Kehl, S.J., McLennan, H., 1983. Excitatory amino acids in synaptic 98 transmission in the Schaffer collateral-commissural pathway of the rat hippo99 campus. J. Physiol. 334, 33–46. 100 Davies, J., Francis, A.A., Jones, A.W., Watkins, J.C., 1981. 2-Amino-5-phosphonovalerate (2APV), a potent and selective antagonist of amino acid-induced and synap101 tic excitation. Neurosci. Lett. 21, 77–81. 102 Douglas, R.M., Goddard, G.V., Riives, M., 1982. Inhibitory modulation of long-term 103 potentiation: evidence for a postsynaptic locus of control. Brain Res. 240, 259–272. 104 Lynch, G., Larson, J., Kelso, S., Barrionuevo, G., Schottler, F., 1983. Intracellular injec105 tions of EGTA block induction of hippocampal long-term potentiation. Nature 106 305, 719–721. 107 108 109 110
Please cite this article in press as: Bliss, T., The NMDA receptor 30 years on, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.04.049
NP5068_proof ■ 8 May 2013 ■ 2/2
2
111 112 113 114 115 116 117
Foreword / Neuropharmacology xxx (2013) 1–2
MacDermott, A.B., Mayer, M.L., Westbrook, G.L., Smith, S.J., Barker, J.L., 1986. NMDAreceptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321, 519–522. McNaughton, B.L., Douglas, R.M., Goddard, G.V., 1978. Synaptic enhancement in fascia dentate: cooperativity among coactive afferents. Brain Res. 157, 277–293. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A., Prochiantz, A., 1984. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465.
Wigström, H., Gustafsson, B., 1985. On long-lasting potentiation in the hippocampus: a proposed mechanism for its dependence on coincident pre- and postsynaptic activity. Acta Physiol. Scand. 123, 519–522.
Tim Bliss Q3 Division of Neurophysiology, National Institute for Medical Research, UK Q1
Please cite this article in press as: Bliss, T., The NMDA receptor 30 years on, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.04.049
118 119 120 121 122 123 124