FUNCTIONAL SWITCH FROM FACILITATION TO INHIBITION IN THE CONTROL OF GLUTAMATE RELEASE BY METABOTROPIC GLUTAMATE RECEPTORS

We have,investigated the role of metabotropic glutamate receptors link ed to phosphoinositide hydrolysis in the control of glutamate release in cerebrocortical nerve terminals. The activation of these receptors with the agonist 3,5-dihydroxyphenylglycine enhanced intrasynaptosomal diacylglycerol and facilitated both the depolarization-induced increa se in the cytosolic free Ca2+ concentration and the release of glutama te. However, 5 min after receptor activation, a second stimulation of the pathway with the agonist failed to produce diacylglycerol and to f acilitate glutamate release. Interestingly, during the period in which the diacylglycerol response was desensitized, a strong agonist-induce d inhibition of Ca2+ entry and glutamate release was observed. This ch ange in the presynaptic effects of 3,5-dihydroxyphenylglycine is rever sible since 30 min after the first stimulation, the agonist-induced in hibition of release disappeared, whereas both the production of diacyl glycerol and the facilitation of glutamate release were recovered. The tonic elevation of the extracellular glutamate concentration from bas al levels (0.8 mu M) up to 5 mu M also produced the switch from facili tation to inhibition in the receptor response. The existence of this a ctivity-dependent switch in the presynaptic control of glutamate relea se suggests that release facilitation is limited to conditions under w hich an appropriate clearance of synaptic glutamate exists, probably t o prevent the neurotoxic accumulation of glutamate in the synapse.