AnoxicLTPsheds light on the multiplefacetsof NMDA receptors C. Hammond, V. Cr~pel, H. Gozlan and Y. Ben-Ari Hippocampal neurones in the CA1 region have become a model system to study the mechanisms of long-term potentiation (LTP) and memory processes. The CA1 region is also highly vulnerable to ischaemic or anoxic episodes which induce a selective and delayed degener- ation of pyramidal neurones. In CA1 neurones, anoxic episodes generate a novel form of LTP to which we refer as anoxic LTP. In common with tetanic LTP, the induction of anoxic L TP is voltage- and NMDA recep- tor-dependent. However, in contrast with tetanic L TP, the expression of anoxic LTP is mediated exclusively by NMDA receptors. These observations suggest that anoxic-ischaemic episodes trigger a switch in favour of NMDA receptor-operated synaptic transmission. We suggest that the multiple forms of NMDA receptor- dependent LTPs are determined by extracellular and intracellular modulatory sites of this receptor. Brief repetitive stimulation of hippocampal afferents generates a persistent enhancement of synaptic trans- mission commonly referred to as long-term poten- tiation (LTP). Typically, LTP is triggered by a tetanic stimulation (100Hz, 1 s); this leads to an increased synaptic efficacy that persists for hours (in vitro) to days to weeks (in vivo). Elucidation of the mechanisms that generate LTP is a major goal of current efforts to clarify the basis of neuronal plasticity, learning and memory process 1'2. In the CA1 region of the hippocampus, from which most of our understanding of LTP is derived, LTP is triggered by the transient enhanced release of gluta- mate 3, the activation of N-methyl-D-aspartate (NMDA)-type receptor-channels, and the rise in intra- cellular calcium concentration [Ca2+]i (for review, see Refs 4 and 5). This initial induction phase occurs within a few seconds of the tetanus 4'5. The rise in [Ca2+]i triggers an expression phase, that is, a persistent enhancement of synaptic efficacy, by a cascade of biochemical and molecular events 1. In physiological conditions, whereas the induction of LTP is mediated by NMDA receptors, the expression is due mostly to a persistent increase of synaptic currents mediated by the other subtype of glutamatergic ionotropic receptors, o~-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors 4'6,7. Therefore, the induction and expression of tetanic LTP involve differ- ent glutamate ionotropic receptors. A variety of procedures increase [Ca2+]i, and an obvious question is whether they also generate LTP. In fact, LTP can be induced by procedures that transiently enhance neural activity and increase [Ca2+]i, including K+-channel blockers 8,9 or a pulse of high-K + medium TM. Moreover, in the CA3 region of the hippocampus, bath application of kainate, bicucul- line, K+-channel blockers or repetitive electrical stimulation (to generate synchronized bursts in CA3 pyramidal neurones) all lead to LTP (for review, see Ref. 11). Seizures are also associated with persistent changes in synaptic efficacy in vivo 11. This suggests that some of the mechanisms involved in the ex- pression of LTP and memory processes might par- ticipate in several pathological conditions. One pathological situation that has raised consider- able interest in this context is ischaemia. The CA1 region of the hippocampus, from which most of our understanding of the mechanisms of LTP derives, is exquisitely susceptible to anoxic-ischaemic episodes 12. In humans and experimental animals, transient global ischaemia induces memory impairment 12 and a selec- tive and delayed degeneration of CA1 pyramidal neurones la in which glutamate receptors and a rise of [Ca2+]i 14 play an important role (see Boxes 1 and 2). We have recently shown that, in the CA1 region, an anoxic-aglycaemic episode also triggers a long-term potentiation of giutamatergic synaptic transmission termed anoxic LTP 15. As for tetanic LTP, the induc- tion of anoxic LTP is triggered by activation of NMDA receptors and a rise of [Ca2+]i, but in contrast to tetanic LTP, the expression of anoxic LTP is also mediated by NMDA receptors. In other words, the induction and expression of anoxic LTP involves the same glutamate ionotropic receptor subtype. There- fore, activation of NMDA receptors can lead to different forms of LTP according to the metabolic status of the neurone. The properties of tetanic and anoxic LTP are compared in this review. We suggest that studies of anoxic LTP will contribute to our understanding of ischaemic cell damage, and possibly also to the devel- opment of novel protective drugs. They also provide a conceptual link between ischaemic insults and memory processes. Finally, they have important consequences on the conceptual framework of LTP research since activation of NMDA receptors can lead to different forms of LTP according to a variety of factors including the metabolic status of the neurone. Since anoxic LTP has been best studied in slices we first briefly describe the effects of anoxia on synaptic transmission in this preparation (for a recent review, see Ref. 16). Effects of anoxia on hippocampal slices A brief anoxic (1-4 rain) or aglycaemic (4-15 rnin) episode rapidly blocks the excitatory postsynaptic potential (EPSP) generated in adult CA1 pyramidal neurones by stimulation of the Schaffer collaterals17-19. In fully submerged slices (2-4 ml rain-1 flow rate) an anoxic episode abolishes the EPSP in less than 2 rain and full recovery occurs within 6-10 rain of reoxy- genation (Fig. 1A and 1B) 17'18. The block of synaptic transmission is irreversible after anoxic episodes last- ing more than 5 min 2°'21. Interestingly, the EPSPs generated in adult CA3 pyramidal neurones or in neonatal CA1 pyramidal neurones are more resistant to anoxic 18'22 or aglycaemic episodes 19 than EPSPs generated in CA1 adult pyramidal neurones, in keeping with the gradient of vulnerability of these neurones to C Hammond, V. Cr~pel, H. 6ozlan and Y. Ben-Ari are at INSERM U29, 123bd PortRoyal,75014 Paris,France. TINS, Vol. 17, NO. 11, 1994 © 1994, ElsevierScience Ltd 497