Distributed synaptic modification in neural networks induced by patterned stimulation

Activity-dependent changes in synaptic efficacy or connectivity are critical for the development(1), signal processing(2) and learning and memory functions(3-6) of the nervous system. Repetitive correlated spiking of pre- and postsynaptic neurons can induce a persistent increase or decrease in synaptic strength, depending on the timing of the pre- and postsynaptic excitation(7-13). Previous studies on such synaptic modifications have focused on synapses made by the stimulated neuron. Here we examine, in networks of cultured hippocampal neurons, whether and how localized stimulation can modify synapses that are remote from the stimulated neuron. We found that repetitive paired-pulse stimulation of a single neuron for brief periods induces persistent strengthening or weakening of specific polysynaptic pathways in a manner that depends on the interpulse interval. These changes can be accounted for by correlated pre- and postsynaptic excitation at distant synaptic sites, resulting from different transmission delays along separate pathways. Thus, through such a 'delay-line' mechanism, temporal information coded in the timing of individual spikes(14-17) can be converted into and stored as spatially distributed patterns of persistent synaptic modifications in a neural network.