Metaplastic facilitation and ultrastructural changes in synaptic properties are associated with long-term modulation...

The neuropeptide substance P evokes a long-term protein synthesis-dependent increase in the cycle frequency of locomotor network activity in the lamprey. Although cellular and synaptic mechanisms that could induce this effect have been identified, nothing is known of the underlying maintenance mechanisms. These mechanisms have been examined here. Substance P potentiates low-frequency-evoked EPSPs from excitatory network interneurons. It also converts the depression of the EPSP during spike trains into facilitation, an example of metaplasticity. The metaplasticity was associated with a reduction of the transmitter release probability but an increase in the number of release sites. Although the potentiation of low-frequency-evoked EPSPs recovered within 1 hr, the metaplastic facilitation had not recovered 3-4 hr after substance P application. The metaplasticity thus extended into the protein synthesis-dependent maintenance phase of the network modulation, making it the only identified cellular or synaptic effect of substance P to last this long. It also had the same induction and maintenance features as the network burst frequency modulation, further suggesting that the two effects were related. Long-term changes in synaptic properties are often associated with changes in synaptic organization. We have thus also examined the effects of substance P on synaptic ultrastructure up to 5 hr after substance P application. Substance P had several significant effects. These included an increase in the number of docked vesicles and a reduction of the synaptic gap. Substance P thus has long-term effects on synaptic organization and function. The relevance of these effects to the long-term locomotor network modulation is discussed.