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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...

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The venom of the funnel-web spider Agelenopsis aperta contains several peptides that paralyze prey by blocking voltage-sensitive calcium channels. Two peptides, omega-Aga-IVB (IVB) and omega-Aga-IVC (IVC), have identical amino acid sequences, yet have opposite absolute configurations at serine 46. These toxins had similar selectivities for blocking voltage-sensitive calcium channel subtypes but different potencies for blocking P-type voltage-sensitive calcium channels in rat cerebellar Purkinje cells as well as calcium-45 influx into rat brain synaptosomes. An enzyme purified from venom converts IVC to IVB by isomerizing serine 46, which is present in the carboxyl-terminal tail, from the L to the D configuration. Unlike the carboxyl terminus of IVC, that of IVB was resistant to the major venom protease. These results show enzymatic activities in A. aperta venom being used in an unprecedented strategy for coproduction of necessary neurotoxins that possess enhanced stability and potency.