Properties and plasticity of paired-pulse depression at a central synapse.

Synaptic depression was studied at the axo-axonic connection between the goldfish Mauthner axon and identified cranial relay interneurons using simultaneous presynaptic and postsynaptic recordings and a paired-pulse stimulus paradigm. We used interstimulus intervals (ISIs) ranging from 10 msec to 1 sec and a cycle time of approximately 5 sec. Depression (Delta EPSP/EPSP1) was maximal at the shorter intervals (80%) and decreased exponentially with a tau approximately 400 msec (360 +/- 107 msec, mean +/- SD). We found the amplitudes of the first and second EPSP were not correlated, indicating the magnitude of depression does not depend on the amount of transmitter released by the conditioning stimulus. At short ISIs, the latency of EPSP2 was 23% longer than that of EPSP1 and recovered to control with tau approximately 400 msec, whereas rise time and decay time were not altered significantly. The latency distribution, which is determined by the timing of the first quantum released each trial, was used to derive alpha(t), the rate of evoked exocytosis after an action potential. alpha(t) was biphasic, and both components were consistently delayed during depression. Presynaptic manipulations of putative intracellular regulatory pathways, such as Ca(2+) and GTPgammaS injections, preferentially affected the amplitude of EPSP1 or EPSP2. These results are not consistent with simple depletion of the available pool of synaptic vesicles as the major mechanism underlying depression. They rather suggest that it is attributable to a modification or refractoriness of the release process and that there may be multiple pathways subserving evoked exocytosis.