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The ubiquitous presynaptic metabotropic glutamate receptors (mGluRs) are generally believed to primarily inhibit synaptic transmission through blockade of Ca 2+  entry. Here, we analyzed how mGluR8 achieves a nearly complete inhibition of glutamate release at hippocampal synapses. Surprisingly, presynaptic Ca 2+  imaging and miniature excitatory postsynaptic current recordings showed that mGluR8 acts without affecting Ca 2+  entry, diffusion, and buffering. We quantitatively compared the Ca 2+  dependence of the inhibition of release by mGluR8 with the inhibition by ω-conotoxin GVIA. These calculations suggest that the inhibition produced by mGluR8 may be explained by a decrease in the apparent Ca 2+  affinity of the release sensor and, to a smaller extent, by a reduction of the maximal release rate. Upon activation of mGluR8, phasic transmitter release toward the end of a train of action potentials is greater as compared with presynaptic inhibition induced by blocking Ca 2+  entry, which is consistent with the important role of Ca 2+  in accelerating the replenishment of released vesicles. The action of mGluR8 was resistant to blockers of classical G-protein transduction pathways including inhibition of adenylate cyclase and may represent a direct effect on the release machinery. In conclusion, our data identify a mode of presynaptic inhibition which allows mGluR8 to profoundly inhibit vesicle fusion while not diminishing vesicle replenishment and which thereby differentially changes the temporal transmission properties of the inhibited synapse.

Depression of Release by mGluR8 Alters Ca 2+ Dependence of Release Machinery