Genetics of Childhood Disorders: LIV. Learning and Memory, Part 7: Maintenance of Long-Term Potentiation

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Before moving on to the processes that contribute to the persistence of long-term potentiation (LTP), we need to address an apparently straightforward issue: which side of the synapse expresses LTP? We have seen that the main events of LTP induction occur in postsynaptic signaling pathways. Does this mean that the locus of LTP expression is also postsynaptic? At the CA3–CA1 synapse, the preponderance of electrophysiological evidence favors the postsynaptic side of the synapse, but this has been a contentious area of research and some data support the hypothesis of increased transmitter release in LTP. The problem of the site of LTP expression has been approached using several different strategies. One method is to determine the rate of glutamate release. The efflux of glutamate from a hippocampal slice can be directly measured, and early work showed an elevation during LTP. However, synaptic release represents only a fraction of total glutamate efflux, and metabolic changes could be largely responsible for the observed increases. A more sophisticated experimental approach exploits the active uptake of synaptic glutamate by glial cells, resulting in graded glial transporter currents that can be recorded. These currents are not increased during LTP, suggesting that the locus of the potentiation is postsynaptic. The hypothesis that LTP expression is restricted to the postsynaptic cell has been challenged by experiments in which vesicle recycling at the CA3–CA1 synapse was monitored using the presynaptic loading of a fluorescent dye. An increase in vesicle recycling would indicate that glutamate-containing vesicles were being turned over at a higher rate, presumably due to increased synaptic release. Such an effect occurred following LTP-inducing stimulation, supporting a presynaptic contribution to the expression of LTP. A second approach to identifying the locus of LTP exploits the voltage-dependent block of N-methyl-D-aspartate (NMDA) receptors described in the previous column, a property that is not shared by (AMPA)-type receptors. This difference can be used to separate the synaptic response into AMPA and NMDA components because the contribution of the NMDA-mediated current will depend upon the postsynaptic membrane voltage. If an increase in glutamate release is responsible for LTP, then the AMPA and NMDA receptor-mediated responses should increase equally. But most studies show that only the AMPA component is potentiated during LTP, consistent with a postsynaptic change that is restricted to AMPA receptors.