Physiological activation of presynaptic metabotropic glutamate receptors increases intracellular calcium and glutamate release

Activation of metabotropic glutamate receptors (mGluRs) has diverse effects on the functioning of vertebrate synapses. The cellular mechanisms that un derlie these changes, however, are largely unknown. The role of presynaptic mGluRs in modulating Ca2+ dynamics and regulating neurotransmitter release was investigated at the vestibulospinal-reticulospinal (VS-RS) synapse in the lamprey brain stem. Application of the specific Group I mGluRs antagoni st 7-( hydroxyimino) cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCO Et) reduced the amplitude of consecutive high-frequency evoked excitatory p ostsynaptic currents (EPSCs). A series of experiments using techniques of e lectrophysiology and calcium imaging were carried out to determine the cell ular mechanisms by which this phenomenon occurs. Concentration-dependent in creases in the pre- and postsynaptic [Ca2+](i) were seen with the applicati on of mGluR agonists. Similarly, high-frequency stimulation of axons caused a Group I mGluR-dependent enhancement in presynaptic Ca2+ transients. Appl ication of mGluR agonist caused a depolarization of the presynaptic element s, while thapsigargin decreased the high-frequency stimulus- and agonist-in duced rises in [Ca2+](i). These data suggest that both membrane depolarizat ion and the release of Ca2+ from intracellular stores potentially play a ro le in mGluR-induced Ca2+ signaling. To determine the effect of this modulat ion of Ca2+ dynamics on spontaneous glutamate release, miniature EPSCs were recorded from postsynaptic reticulospinal neurons. A potent Group I mGluR agonist, (S)-homoquisqualic acid, caused a large increase in the frequency of events. These results demonstrate the presence of presynaptic Group I mG luRs at the VS-RS synapse. Activation of these receptors leads to a rise in [Ca2+](i) and enhances the spontaneous and evoked release of glutamate. Ta ken together, these studies highlight the importance of synaptic activation of these facilitatory autoreceptors in both shortterm plasticity and synap tic transmission.