Differential regulation of transmitter release by presynaptic and glial Ca2+ internal stores at the neuromuscular synapse

Abstract

The differential regulation of synaptic transmission by internal Ca2+ stores of presynaptic terminals and perisynaptic Schwann cells (PSCs) was studied at the frog neuromuscular junction. Thapsigargin (tg), an inhibitor of Ca2+-ATPase pumps of internal stores, caused a transient Ca2+ elevation in PSCs, whereas it had no effect on Ca2+ stores of presynaptic terminals at rest. Tg prolonged presynaptic Ca2+ responses evoked by single action potentials with no detectable increase in the resting Ca2+ level in nerve terminals. However, Ca2+ accumulation was observed during high frequency stimulation. Tg induced a rapid rise in endplate potential (EPP) amplitude, accompanied by a delayed and transient increase. The effects appeared presynaptic, as suggested by the lack of effects of tg on the amplitude and time course of miniature EPPs (MEPPs). However, MEPP frequency was increased when preparations were stimulated tonically (0.2 Hz). The delayed and transient increase in EPP amplitude was occluded by injections of the Ca2+ chelator BAPTA into PSCs before tg application, whereas a rise in intracellular Ca2+ in PSCs induced by inositol 1,4,5-triphosphate (IP3) injections potentiated transmitter release. Furthermore, increased Ca2+ buffering capacity after BAPTA injection in PSCs resulted in a more pronounced synaptic depression induced by high frequency stimulation of the motor nerve (10 Hz/80 sec). It is concluded that presynaptic Ca2+ stores act as a Ca2+ clearance mechanism to limit the duration of transmitter release, whereas Ca2+ release from glial stores initiates Ca2+-dependent potentiation of synaptic transmission.