Activation of metabotropic glutamate receptors induces periodic burst firing and concomitant cytosolic Ca2+ oscillations in cerebellar interneurons.

Little is known about the generation of slow rhythms in brain neuronal circuits. Nevertheless, a few studies, both from reconstituted systems and from hippocampal slices, indicate that activation of metabotropic glutamate receptors (mGluRs) could generate such rhythms. Here we show in rat cerebellar slices that after either release of glutamate by repetitive stimulation, or direct stimulation of type 1 mGluRs, molecular layer interneurons exhibit repetitive slow Ca(2+) transients. By combining cell-attached patch-clamp recording with Ca(2+) imaging, we show that the regular Ca(2+) transients (mean frequency, 35 mHz induced by 2 microm quisqualate in the presence of ionotropic glutamate receptor blockers) are locked with bursts of action potentials. Nevertheless, the Ca(2+) transients are not blocked by tetrodotoxin, indicating that firing is not necessary to entrain oscillations. The first Ca(2+) transient within a train is different in several ways from subsequent transients. It is broader than the subsequent transients, displays a different phase relationship to associated spike bursts, and exhibits a distinct sensitivity to ionic and pharmacological manipulations. Whereas the first transient appears to involve entry of Ca(2+) ions through transient receptor potential channel-like channels and secondarily activated L-type Ca(2+) channels, subsequent transients rely mostly on an exchange of Ca(2+) ions between the cytosol and D-myo-inositol-1,4,5-triphosphate-sensitive intracellular Ca(2+) stores. The slow, highly regular oscillations observed in the present work are likely to drive pauses in postsynaptic Purkinje cells, and could play a role in coordinating slow oscillations involving the cerebello-olivar circuit loop.