Inhibitory transmission controls the action potential firing rate and pattern of Purkinje cell activity in the cerebellum. A long-term change in inhibitory transmission is likely to have a profound effect on the activity of cerebellar neuronal circuits. However, little is known about how neuronal activity regulates synaptic transmission in GABAergic inhibitory interneurons (stellate/basket cells) in the cerebellar cortex. We have examined how glutamate released from parallel fibers (the axons of granule cells) influences postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in stellate cells and modulates gamma-aminobutyric acid (GABA) release from these neurons. First, we found that burst stimulation of presynaptic parallel fibers changes the subunit composition of post-synaptic AMPA receptors from GluR2-lacking to GluR2-containing receptors. This switch reduces the Ca(2+) permeability of AMPA receptors and the excitatory postsynaptic potential amplitude and prolongs the duration of the synaptic current, producing a qualitative change in synaptic transmission. This switch in AMPA receptor phenotype can be induced by activation of extrasynaptic N-methyl-D: -aspartate (NMDA) receptors and involves PICK1 and the activation of protein kinase C. Second, activation of presynaptic NMDA receptors triggers a lasting increase in GABA release from stellate cells. These changes may provide a cellular mechanism underlying associative learning involving the cerebellum.