Hippocampal long-term potentiation (LTP) is a remarkably stable facilitation of synaptic responses resulting from very brief trains of high-frequency stimulation. Because of its persistence and modest induction conditions, LTP represents a promising candidate for a substrate of memory. Some progress has been made in localizing the changes responsible for the effect; for example, it has been shown that LTP is not accompanied by changes in the fibre volleys of the test afferents or by generalized alterations of the dendrites of their target cells. However, it is unknown whether the potentiation is due to pre- or postsynaptic changes and there is evidence in favour of each (for example, see refs 5, 6). We now report that intracellular injections of the calcium chelator EGTA block the development of LTP. These results strongly suggest that LTP is caused by a modification of the postsynaptic neurone and that its induction depends on the level of free calcium.
A combination of current-and voltage-clamp techniques applied to hippocampal brain slices was used to evaluate the role of postsynaptic electrogenesis in the induction of associative synaptic enhancement. In accordance with Hebb's postulate for learning, repetitive postsynaptic spiking enabled enhancement in just those synapses that were eligible to change by virtue of concurrent presynaptic activity. However, the essential postsynaptic electrogenic event that controlled the enhancement was shown to involve biophysical processes that were unknown when Hebb formulated his neurophysiological postulate. The demonstrated spatiotemporal specificity of this pseudo-Hebbian conjunctive mechanism can account qualitatively for the known neurophysiological properties of associative long-term potentiation in these synapses, which in turn can explain the "cooperativity" requirement for long-term potentiation. (3,8,9), and experiential influences on visual system development (2,3,(10)(11)(12). In spite of the considerable historical and contemporary interest in this hypothesized form of use-dependent synaptic modification, there has been no direct experimental demonstration that Hebbian synapses exist (2, 13).In the present study we examined the possibility that a Hebbian conjunctive mechanism might underlie associative long-term potentiation (LTP) in regio superior of the hippocampus (ref. 14; see also refs. 15-17). Brief, high-frequency stimulation of a weak synaptic (W) input to this region induces a persistent synaptic enhancement in that pathway only if another, sufficiently strong synaptic (S) input to the same region is activated at about the same time (refs. 14, 18-20; see also refs. 15-17). In a manner reminiscent of Pavlovian conditioning, associative LTP can be selectively induced in either of two separate W inputs by varying the temporal relationship between their activity relative to activity in the S input (20). The mechanism underlying associative LTP has been proposed to mediate certain of the suspected mnemonic functions of the hippocampus (20).These features of associative LTP can easily be explained by a Hebbian mechanism. According to this interpretation, the postsynaptic currents produced by stimulating the S input allow the required coincidence between activity in the W input and the postsynaptic cell. An alternative possibility is that the essential contribution of activity in the S input is unrelated to consequences ofpostsynaptic depolarization but instead involves the concomitant release of a critical amount of a necessary "LTP factor" (ref. 21, cf. ref. 22). To evaluate these possibilities, in the present experiments we substituted for the usual S input a combination of current-and voltageclamp procedures that either forced or prevented simultaneous pre-and postsynaptic activity. MATERIALS AND METHODSPreparation and Maintenance of Slices. Hippocampal slices were prepared from male Sprague-Dawley rats in the usual manner (14,20,23) and maintained at 30-320C in a perfusion chamber. The bat...
SUMMARY1. N-Methyl-D-aspartate (NMDA) receptors were expressed in Xenopus oocytes injected with rat brain RNA. The modulation of NMDA-induced currents was examined by activating protein kinase C (PKC) either directly (using phorbol esters) or indirectly (via metabotropic glutamate agonists).2. Bath application of the PKC activator, 4-,f-phorbol-12,13-dibutyrate (PDBu) resulted in a two-fold increase in the NMDA-evoked current at all holding potentials examined (-80 to 0 mV). The inactive (a) stereoisomer of phorbol ester was ineffective.3. The increase was observed under conditions that eliminate the oocyte's endogenous calcium-dependent chloride current, which often contributes to the NMDA response in oocytes. 4. The PDBu effect was specific to the NMDA subclass of glutamate receptors in that no increase was observed in the responses to two other glutamate agonists, kainate and AMPA (ac-amino-3-hydroxy-5-methylisoxazole-4-propionic acid).5. Stimulation of PKC by activation of metabotropic receptors via either quisqualate or trans-ACPD (trans-1-aminocyclopentane-1,3-dicarboxylic acid) also led to an increase in NMDA currents.6. Both methods of enhancement induced transient effects. PDBu effects lasted 10-45 min, depending upon both dose and length of application. Quisqualate and trans-ACPD effects were shorter, lasting less than 10 min under these conditions of application. 7. Both methods of enhancement were blocked by the PKC inhibitor, staurosporine. In addition, the phorbol ester-induced enhancement of NMDA responses occluded further enhancement by quisqualate.8. The results suggest a role for metabotropic glutamate receptors in modulation of NMDA-mediated processes.
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