PRESYNAPTIC FACILITATION REVISITED - STATE AND TIME-DEPENDENCE

The mechanisms underlying short-term presynaptic facilitation, the enh ancement of transmitter release from sensory neurons in Aplysia, induc ed by serotonin (5-HT), can be divided into two categories: (1) change s in ionic conductances leading to spike broadening and enhancement of Ca2+ influx; and (2) actions on the machinery for transmitter release that are independent of spike broadening and the resulting increases in Ca2+ influx. Spike broadening and the associated enhancement of exc itability are induced by the modulation of K+ conductances in the sens ory neuron. The cellular mechanisms that contribute to the enhancement of release that is independent of spike broadening are not known and may involve vesicle mobilization or other steps in exocytotic release. These two facilitatory actions of 5-HT are mediated by at least two s econd-messenger-activated protein kinase systems, protein kinase A (PK A) and protein kinase C (PKC). These two second-messenger cascades ove rlap in their contributions to synaptic facilitation. However, their r elative contributions to enhancement of transmitter release are not si mply synergistic but are state- and time-dependent. The state dependen ce is a reflection of the synapse's previous history of activity. When the synapse is rested (and not depressed), a brief pulse of 5-HT (las ting from 10 sec to 5 min) produces its actions primarily through PKA via both spike broadening-dependent and -independent mechanisms. The b roadening primarily involves the modulation of a voltage-dependent KC current, I-KV, with a small contribution by a voltage-independent K+ c urrent, I-KS. By contrast, the enhancement of excitability is mediated primarily by the modulation of I-KS. As the synapse becomes depressed with repeated activity, the contribution of PKC becomes progressively more important. As is the case with PKA, PKC produces its action both by broadening the spike via modulation of I-KV and by a spike broaden ing-independent mechanism. In addition to being state-dependent, the m echanisms of facilitation are time-dependent. There are differences in the response to 5-HT when it is given briefly to produce short-term f acilitation or when the exposure is prolonged. When exposure is brief (less than or equal to 5 min), PKA dominates. When exposure is prolong ed (10-20 min), PKC becomes dominant as it is with depressed synapses. Thus, synaptic plasticity appears to be expressed in several overlapp ing time domains, and the transition between very short-term facilitat ion and various intermediate duration phases seems to involve interact ive processes between the kinases.