GABA_B receptor-mediated presynaptic inhibition has history-dependent effects on synaptic transmission during physiologically relevant spike trains

Presynaptic inhibition is a form of neuromodulation that interacts with activity-dependent short-term plasticity so that the magnitude, and sometimes even the polarity, of that activity-dependent short-term plasticity is changed. However, the functional consequences of this interaction during physiologically relevant spike trains are poorly understood. We examined the effects of presynaptic inhibition on excitatory synaptic transmission during physiologically relevant spike trains, using the GABA_B receptor (GABA_BR) agonist baclofen to engage presynaptic inhibition and field EPSPs (fEPSPs) in hippocampal slices to monitor synaptic output. We examined the effects of baclofen on the relationship between an fEPSP during the spike train and the timing of spikes preceding that fEPSP, a relationship that we refer to as the history dependence of synaptic transmission. Baclofen alters this history dependence by causing no inhibition during short interspike intervals (ISIs) in the spike train but a maximal inhibition during long ISIs. This effect strengthens the dependence of the fEPSP on the first ISI preceding it. One consequence of this effect is that the apparent affinity of baclofen is strongly reduced during physiologically relevant spike trains when compared with conventional stimulus paradigms, and a second consequence is that the overall inhibition experienced by a synapse will vary considerably during repeated trials of a behavioral task. We conclude that GABA_BR-mediated presynaptic inhibition is more accurately described as a high-pass filter than as a simple inhibition, and that this filtering must be taken into account to accurately assess the effects of presynaptic inhibition under physiologically relevant conditions.