Presynaptic metabotropic glutamatergic regulation of inhibitory synapses in rat cerebellar slices.

1. The effects of the metabotropic glutamate agonist trans-ACPD (t-ACPD) were investigated in various locations of the inhibitory network made by GABAergic interneurones in the molecular layer of rat cerebellar slices. 2. t-ACPD exerted complex effects on spontaneous IPSCs in Purkinje cells. IPSC frequency was transiently inhibited during short (< 1 min) applications, and enhanced upon washing. During prolonged exposure to t-ACPD, IPSCs became organized in high-frequency bursts interspersed with periods of deep inhibition. 3. In interneurones, the frequency of spontaneous IPSCs was enhanced by t-ACPD. As in Purkinje cells, spontaneous IPSCs had a tendency to cluster in bursts in the presence of t-ACPD. 4. Evoked IPSCs recorded either in interneurones or in Purkinje cells upon stimulation of presynaptic interneurones were reversibly inhibited by t-ACPD. 5. Miniature IPSCs (mIPSCs) were recorded in the presence of tetrodotoxin both in Purkinje cells and in interneurones. t-ACPD did not alter the mean amplitude of mIPSCs in either cell type. It reduced the frequency of mIPSCs in Purkinje cells, but did not alter their rate in interneurones. 6. In cell-attached recordings on interneurone somata, t-ACPD was found to induce clustering of action potentials and to enhance the mean rate of firing. These results apply whether t-ACPD was tested in normal saline, in the presence of glutamatergic ionotrophic blockers, or in the presence of a mixture of glutamatergic and GABAergic blockers. 7. The results suggest that t-ACPD has at least two different modes of action. One effect is to alter the intrinsic firing rate of interneurones, presumably through an action on somatic conductance mechanisms. The other is to decrease the efficacy of the interneurone-interneurone and interneurone-Purkinje cell synapses, presumably through an action on axonal conductance systems and/or vesicle release mechanisms.