Theta pattern stimulation and the induction of LTP: the sequence in which synapses are stimulated determines the degree to which they potentiate.

Induction of long-term potentiation (LTP) by asynchronous stimulation of converging afferents was studied in hippocampal slices. Three stimulation electrodes were positioned to activate separate groups of Schaffer-commissural inputs to a population of CA1 pyramidal cells. Patterned stimulation consisted of a single coincident priming pulse to all 3 electrodes followed by a burst of 4 pulses (100 Hz) to the first input (S1) at a delay of 180 ms, to the second (S2) at a delay of 200 ms, and to the third (S3) at a delay of 220 ms. This pattern was repeated 10 times at 5-s intervals. The magnitude of LTP induced (measured 20 min after stimulation) was greatest for the first stimulated input, intermediate for the second, and least for the third. Intracellular recordings indicated that the greatest postsynaptic depolarization occurred during the period of S2 stimulation; thus the magnitude of LTP induced was not simply dependent on the degree of depolarization during afferent activation. Rather, sustained depolarization after synaptic activation could contribute to LTP induction by prolonging the activity of N-methyl-D-aspartate receptor-gated channels. Earlier-arriving bursts may also trigger an inhibitory process that reduces the effectiveness of later bursts for inducing LTP.