Progress on LTP at hippocampal synapses: a post-synaptic Ca2+ trigger for memory storage?

he strength of transmission at many synapses increases with repetitive use. When the increase in strength lasts for more than a few minutes, it is called long-term potentiation, or LTP. LTP has been studied most extensively at excitatory synapses onto principal neurons of the hippocampal forma- tion, where it was first described by L0mo in 1966 ~-3. Because hippo- campal LTP can be triggered by less than one second of intense synaptic activity but lasts for hours or much longer, it has been recognized as a possible experi- mental model for memory storage. This short review will describe some recent observations that illuminate a novel mechanism that appears to couple synaptic activity to LTP triggering. A postsynaptic ion channel evidently detects tem- poral contiguity of pre- and post- synaptic activity and signals this contiguity by allowing post-synaptic entry of calcium ions. It may be significant that this mechanism embodies formal characteristics of a general mechanism postulated by Hebb in 1948 as a likely basis for memory storage and learning. LTP processes, types, receptors and channels Three criteria help to circum- scribe the selective treatment of hippocampal LTP given here: (1) At least three different pro- cesses or aspects of LTP can be recognized, and correspondingly three types of questions can be asked: (A) triggering (how is use of a synapse transduced into an effective biochemical signal?); (B) expression (which step in synaptic transmission is potentiated?); and (C) maintenance (which molecules are responsible for the actual, long- term storage of information about past use?). The focus here will be mainly on new results pertinent to the triggering process. (2) It now appears that different mechanisms may underlie LTP at different synapses, even within the confines of the hippocampal forma- tion. For instance, LTP at the mossy-fiber synapses onto the CA3 principal cells involves a mechanism distinctively different from that observed in CA1, dentate gyms and other CA3 synapses 4. Here we shall consider mainly results obtained in the CA1 region, with some reference to results from apparently similar dentate region synapses. Unfortunately, it will not be possible here to treat any of the intriguing results from the mossy fiber-CA3 synapse (see for example Refs 5, 6). (3) The transmitter candidate at the CA1 excitatory synapse is the amino acid glutamate, and at least two types of glutamate receptor must be distinguished: the NMDA type (so named for N-methyl-D- aspartate, a selective agonist) and the kainate type (named for its own selective agonist). Both types of receptor open ion channels in response to glutamate and both are present postsynaptically 7-9. The ion channels opened by the two different receptors have distinct permeation properties, so they can be designated NMDA channels and kainate channels. The kainate channel appears to carry most of the postsynaptic current during normal synaptic transmission 8, but the NMDA channel is of central interest here because of its possible role in triggering LTP. Post-synaptic triggering of LTP In principle, LTP could be triggered in response to either pre- or post-synaptic activity, and both models have been proposed 3'1°. However, there has been in- creasing evidence that a crucial triggering step is indeed post- synaptic 11'~e. Early indications oI this came from interactions of mul- tiple synaptic inputs that seemed most readily explained at the postsynaptic leveP :~q7. In addition, the NMDA channel blocker 2- amino-5-phosphonovalerate (APV) was found to block LTP triggering without blocking the expression of previously established LTP s'9. As- suming that APV can only act postsynapticaily, this finding also suggested that a postsynaptic step is necessary in LTP triggering, as well as immediately implicating NMDA receptors in the process. In addition, the finding that injection of the Ca2+-chelating agent, EGTA, into postsynaptic ceils suppresses LTP onset further implicates a postsynaptic component; in par- ticular, one involving a transient Ca 2+ signal that can be suppressed by FGTA ts. Important new insights about LTP triggering have recently been provided by electrophysiological studies from three groups 19-m. In these experiments, membrane potential in postsynaptic cells was manipulated independently of synaptic input through use of intracellular current-passing micro- electrodes, in some cases using voltage-clamp circuitry. Normally, the synaptic inputs leading to LTP would by themselves produce a large postsynaptic depolarization, mainly due to opening of the kainate channels. However, when similar postsynaptic depolarizations were produced by microelectrode cur- rent (without synaptic input), LTP was not triggered 21. Nonetheless, postsynaptic membrane potential was found to have a profound effect on LTP triggering when synaptic inputs are present. Hyperpolar- ization during intense synaptic input blocked triggering of LTP that otherwise would have occur- red 2°'2~. Conversely, depolariza- tion during less intense inputs promoted LTP triggering that otherwise would not have occurred with these weak inputs 1°. These findings constitute strong evidence for a postsynaptic trigger- ing mechanism. The effect of postsynaptic potential would be very difficult to explain with any purely presynaptic model for LTP triggering. The ready reversibility of the experimental treatments (postsynaptic hyperpolarization or depolarization) permitted elegant controls, which reinforce all three sets of studies. In addition, these experiments demonstrate that it is not postsynaptic potential