In recent years, it has become clear that, in addition to conventional anterograde transmission, signaling in neural circuits can occur in a retrograde manner. This suggests the additional possibility that postsynaptic release of neurotransmitter might be able to act in an autocrine fashion. Here, we show that brief depolarization of a cerebellar Purkinje cell triggers a slow inward current. This depolarization-induced slow current (DISC) is attenuated by antagonists of mGluR1 or TRP channels. DISC is eliminated by a mixture of voltage-sensitive Ca 2؉ channel blockers and is mimicked by a brief climbing fiber burst. DISC is attenuated by an inhibitor of vesicular glutamate transporters or of vesicular fusion. These data suggest that Ca 2؉ -dependent postsynaptic fusion of glutamate-loaded vesicles evokes a slow inward current produced by activation of postsynaptic mGluR1, thereby constituting a useful form of feedback regulation.Ca channel ͉ retrograde signaling ͉ vesicular fusion R etrograde signaling in neural circuits is often triggered by a postsynaptic Ca 2ϩ flux driven by activity. This can evoke the release of two broad classes of signal: those triggered by Ca 2ϩ -sensitive enzymatic synthesis, like NO and endocannabinoids (although in some cases, endocannabinoid synthesis is Ca 2ϩ -independent), and those that require postsynaptic vesicular fusion, like classical neurotransmitters and peptide hormones. In the olfactory bulb, it is well established that action potential invasion of mitral cell dendrites triggers dendritic glutamate release, which then excites the dendrites of adjacent granule cells (1). In other brain regions, such as neocortical layer 2/3 pyramidal cells, the postsynaptic release of glutamate has been inferred from experiments in which postsynaptic depolarization triggers a depression of inhibitory postsynaptic potentials (IPSPs) or inhibitory postsynaptic currents (IPSCs) evoked by activation of fast-spiking interneurons. In these experiments, this effect was blocked by postsynaptic Ca 2ϩ chelation, manipulations to interfere with the loading or fusion of postsynaptic glutamate-containing vesicles, or blockade of group II mGluRs (presumably located on the interneuron terminals), but not by antagonists of CB1 receptors (2, 3).Cerebellar Purkinje cells release GABA from axonal terminals, but it has been suggested they may also release glutamate from their dendrites and/or soma (4). Brief depolarization of Purkinje cells triggered a persistent increase in the frequency of mIPSCs, a phenomenon termed depolarization-induced potentiation of inhibition (DPI). DPI was blocked by postsynaptic Ca 2ϩ chelation or treatments that blocked SNARE-dependent vesicular fusion (Botulinum toxin B, GDPbetaS). In addition, bath application of an NMDA receptor antagonist but not a CB1 receptor antagonist blocked DPI. It was proposed that Ca 2ϩ -triggered fusion of vesicles in Purkinje cell dendrites released glutamate, which then diffused to activate NMDA receptors on interneuron terminals (4, 5). If this mod...