No abstract

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...

There is conflicting evidence regarding the issue of whether NMDA receptors in the basolateral amygdalar complex (BLA) are critically involved in the expression of conditioned fear. This matter was addressed by infusing the rat BLA with D,L-2-amino-5-phosphonovaleric acid (APV), a competitive NMDA receptor antagonist. APV infusion into the BLA was reported to block the expression of conditioned fear when measured by freezing but not when measured by fear-potentiated startle response to a loud noise. To examine this issue further, here we used multiple indices of conditioned fear, including analgesia, 22 kHz ultrasonic vocalization (USV), defecation, and freezing. Rats with bilateral BLA cannula implants underwent fear conditioning consisting of 10 tone-footshock pairings. Before context and tone fear-retention tests, animals received intra-BLA infusions with APV (2.5 g/side) or artificial CSF. Both tone and context tests demonstrated that the expression of conditioned freezing, USV, defecation, and analgesia were significantly impaired by intra-amygdalar infusions of APV. In a second set of experiments, intra-BLA infusions of APV markedly impaired the normal expression of postshock fear responses during training, as measured by freezing, USV, and defecation. Immediate postshock fear expression was predictive of subsequent fear retention to the tone and context when the animals were not infused. These results are consistent with the hypothesis that amygdalar NMDA receptors participate in normal synaptic transmission and therefore the overall functioning of the amygdala.

Long-term synaptic potentiation (LTP) is a leading candidate for a synaptic mechanism of rapid learning in mammals. LTP is a persistent increase in synaptic efficacy that can be quickly induced. The biophysical process that controls one type of LTP is formally similar to a synaptic memory mechanism postulated decades ago by the psychologist Donald Hebb. A key aspect of the modification process involves the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. This ionophore allows calcium influx only if the endogenous ligand glutamate binds to the NMDA receptor and if the voltage across the associated channel is also sufficiently depolarized to relieve a magnesium block. According to one popular hypothesis, the resulting increase in the intracellular calcium concentration activates protein kinases that enhance the postsynaptic conductance. Further biophysical and molecular understanding of the modification process should facilitate detailed explorations of the mnemonic functions of LTP.