Long-term depression (LTD) at the parallel fiber-Purkinje cell synapse in the cerebellum is a well-known example of synaptic plasticity. Although LTD is thought to reflect an enduring loss of postsynaptic AMPA receptor sensitivity, the underlying mechanisms are unclear. Protein-tyrosine kinases (PTKs) are able to modulate ionotropic receptor function and are enriched in Purkinje cells. Using intracellular recording from Purkinje cells, it is shown that two structurally and mechanistically distinct PTK inhibitors, lavendustin A and herbimycin A, block LTD induced by pairing parallel fiber stimulation with postsynaptic Ca2+ spiking. Intracellular application of the protein kinase C (PKC) activator, (-)-indolactam V, consistently depressed parallel fiber-Purkinje cells EPSPs and occluded pairing-induced LTD. Herbimycin A nullified the run-down produced by (-)-indolactam V. These data suggest that PTKs are necessary for LTD at the parallel fiber-Purkinje cell synapse and that PKC-induced synaptic depression requires PTK activity.