Long-term potentiation and the computational synapse.

Not all synapses in the brain are the same. Some transmit signals from one neuron to the next more efficiently than others; the efficiency is referred to as synaptic strength. Currently the most widely accepted theory of memory is that memories are stored as patterns of synaptic strength. Longterm potentiation (LTP) is one way that the strength of synapses is changed and perhaps memories are encoded. Because of this, LTP is one of the most widely studied topics of neuroscience research. In particular, LTP in the mammalian hippocampus has been the focus of intensive research by many scientists, as well as the source of considerable controversy. Although a great deal of effort has been devoted to elucidating the mechanism of LTP expression in the CA1 region of hippocampus, other exciting questions concerning LTP are addressed by two papers in this issue of the Proceedings. Min et al. (1) investigate synapses in the dentate gyrus region of the hippocampus, and ask the question ‘‘Do synapses from the two input pathways with different properties exhibit the same type of LTP?’’ For synapses in CA1, Peterson et al. (2) raise the critical question ‘‘Are changes in synaptic strength graded or all-or-none?’’ The hippocampus is a popular site for electrophysiology research because most of its primary cell types are separated into easily recognizable regions, and the axonal fiber tracts connecting these regions are relatively simple and well defined, as illustrated in Fig. 1. In the dentate gyrus the principal cell type is the granule cell, and the majority of granule cell input comes from a fiber tract called the perforant path. The perforant path contains axons that originate in the entorhinal cortex and provide a major sensory input to the hippocampus. The perforant path splits into two anatomically distinct pathways, called the medial perforant path and the lateral perforant path. These fibers form excitatory synapses on the middle third and outer third (respectively) of the granule cell dendritic tree. This anatomical organization enables the study of two different populations of synapses onto the same cell type using extracellular stimulation. Axons in the medial and lateral perforant pathways originate from different regions of the entorhinal cortex and carry different kinds of sensory inputs (3). The locations of the medial and lateral perforant path are shown in Fig. 1; the two types of synapses studied by Min et al. (1) are represented in red (medial) and yellow (lateral). The two types of synapses are similar in that they both release the neurotransmitter glutamate, and, like most cortical synapses, contain two types of postsynaptic glutamate receptors, NMDA and AMPA receptors. At these synapses, like others, neurotransmitter is released probabilistically; stimulating the synapse may cause either transmitter release or no transmitter release. But differences between the medial and lateral synapses also have been found. Many pharmacological manipulations produce markedly different results in the two populations (4–7). Physiological differences occur as well (8, 9). For example, synapses in the medial perforant path grow weaker (are less likely to release transmitter) on the second of two closely spaced stimuli, whereas synapses in the lateral pathway grow stronger with the same stimulus pair (10). Furthermore, the two pathways are different in terms of the stimulation needed to induce LTP (11). In the current paper, Min et al. (1) address the important question of whether the differences between the inputs from these two pathways represent two distinct forms of LTP. They use a trick for estimating the probability that stimulation causes transmitter release, and see if the probability is increased by LTP. The trick is to add a drug that only blocks synapses that release transmitter, and see how quickly the synapses are blocked. The drug, MK-801, acts at NMDA receptors and irreversibly blocks synapses where transmitter has been released (12). The rate of MK-801 blocking therefore is related to transmitter release probability: faster blocking indicates an increase in release probability, whereas a slower rate indicates a decrease (13, 14). A key finding of this paper is that LTP causes an significant increase in the MK-801 blocking rate in synapses from the medial path, whereas no change was observed in the blocking rate in the lateral path synapses (1). The authors conclude that LTP in the medial perforant path is accompanied by an increase in neurotransmitter release probability. Their interpretation of the results from the lateral path, however, is more complex. Although the LTP in the lateral path appears to be different, the authors point out that in the lateral path an increase in release probability after LTP still could be present, but difficult to detect using the MK-801 method. To explain this, they invoke the currently popular hypothesis of intersynaptic cross-talk. To understand this possibility, we need to take a step back and review the meaning of ‘‘intersynaptic cross-talk.’’ Intersynaptic cross-talk refers to the idea that neurotransmitter released by one synapse may spill over and be detected by a neighboring synapse. This would involve transmitter diffusing out of the synaptic cleft and over to a neighboring cleft in a high enough concentration to activate postsynaptic receptors. The idea of intersynaptic cross-talk challenges the traditional assumption that a synapse is a private connection between an axon and a dendrite, and that all synapses act independently of each other. Excitatory synapses in cortex are on average, however, only separated from a neighboring synapse by 1 mm, and because glutamate can diffuse on the order of 1 mm2ymsec, the idea of glutamate spillover is not unreasonable. NMDA receptors have an affinity for glutamate, which is two orders of magnitude greater than that of AMPA receptors (15). In addition, NMDA receptors are tonically activated by baseline levels of exogenous glutamate (16). As a result, NMDA receptors are more likely to be affected by glutamate spillover than AMPA receptors. Consequently, synaptic transmission involving AMPA receptors could have little or no cross-talk, whereas synaptic transmission mediated by NMDA receptors could involve much more cross-talk. Min et al. (1) measured a greater amount of transmitter sensed by the NMDA receptors than the AMPA receptors in the lateral perforant path synapses, which supports the idea of glutamate spillover selectively activating neighboring NMDA receptors in these synapses. This same result has been shown recently at the CA3 to © 1998 by The National Academy of Sciences 0027-8424y98y954086-3$2.00y0 PNAS is available online at http:yywww.pnas.org.