Characterization of depolarization-induced suppression of inhibition using paired interneuron--Purkinje cell recordings.

Depolarization-induced suppression of inhibition (DSI) is a retrograde form of synaptic inhibition involving the Ca2+-dependent release of cannabinoids from the postsynaptic cell. DSI exerts multiple effects on presynaptic neurons: here, we establish the breakdown of DSI in its individual components at the synapses between basket and stellate cells and Purkinje cells. In the presence of tetrodotoxin, the change in IPSC frequency entirely accounted for the decrease of transmission during DSI; in contrast, without tetrodotoxin, the reductions of frequency and average amplitude gave equal contributions. In paired recordings, transmission displayed an irreversible rundown unless interneurons were recorded from with the perforated patch method. Under these conditions, a DSI of 68.8% was measured; the failure rate and the paired pulse ratio (at 20 msec intervals) increased from 1.2 to 20.2 and 95.6 to 132.6%, respectively, and the variance to mean ratio augmented 2.17-fold. Presynaptic dialysis with Cs+ led to a major potentiation of synaptic strength and to a marked reduction of DSI with respect to control potassium conditions; DSI recovered only partially when decreasing the extracellular Ca2+ concentration to match the control IPSC amplitudes. These results, combined with those of Kreitzer et al. (2002), indicate that three distinct presynaptic processes contribute to DSI: reductions of miniature frequency (13.4% of total DSI), of presynaptic action potential frequency (23.2%), and of the probability that presynaptic depolarizations elicit transmitter release (63.4%). The latter component involves a modulation of K+ channels and trial-to-trial modifications of the presynaptic signal.