Long-term depression (LTD) at cerebellar parallel fiber (PF)-Purkinje cell synapses must be balanced by long-term potentiation (LTP) to prevent saturation and allow reversal of motor learning. The only previously analyzed form of cerebellar LTP is induced by 4 -8 Hz PF stimulation and requires cAMP but not nitric oxide. It is a poor candidate to reverse LTD because it is presynaptically expressed whereas LTD is postsynaptic. We now characterize a new form of LTP induced by 1 Hz PF stimulation for at least 300 s. This LTP is postsynaptically expressed, enhanced by chelating postsynaptic Ca 2؉ , and depends on nitric oxide but not cAMP or cGMP, making it a plausible anti-Hebbian counterpart to Hebbian LTD.T he cerebellar cortex plays a crucial role in a wide variety of behavioral modifications, of which Pavlovian conditioning of eyelid blinking and gain modulation of the vestibuloocular reflex have been the most extensively studied (see refs. 1-4 for reviews). In the cerebellar cortex, the most extensively investigated form of synaptic plasticity has been long-term depression (LTD) of the glutamatergic synapses from parallel fibers (PFs) onto Purkinje cells (PCs). PF-PC LTD is associative (requires concurrent pre-and postsynaptic activity) and fairly synapsespecific (5), requires postsynaptic Ca 2ϩ elevation, and is expressed postsynaptically. Coincidence of the postsynaptic Ca 2ϩ with nitric oxide (NO), normally generated presynaptically and diffusing anterogradely, is necessary and sufficient for a major form of LTD in young adult cerebellar slices; NO acts via cGMP and protein kinase G (6-9). However, the PF-PC synapse also needs long-term potentiation (LTP), driven by presynaptic activity without postsynaptic depolarization, to prevent saturation of LTD, allow extinction of learned associations, and refine the temporal precision of learned responses (10-12). Although a few examples of LTP at the PF-PC synapse had been anecdotally reported in articles focusing on LTD (8, 13-16), the first systematic characterization of LTP was by Salin et al. (17), who stimulated the PFs 120 times at 4-8 Hz and observed a subsequent 40-50% long-term enhancement of excitatory postsynaptic potentials. This work and several subsequent studies have shown that such LTP is induced and expressed presynaptically by means of cAMP signaling (18-21).Although cAMP-mediated presynaptic LTP clearly exists, it remains an unattractive solution to the problem of resetting postsynaptically expressed LTD, because the two processes are expressed in different locations and cannot truly reverse each other (10, 11). Also, presynaptic LTP is independent of the presence or absence of PC activity (17,19). During our studies of associative LTD evoked in young adult slices by coincident increases in Ca 2ϩ , NO, and cGMP during 1-Hz stimulation for 30 s, we sometimes observed small LTP when LTD was blocked by chelation of postsynaptic Ca 2ϩ or inhibition of protein kinase G (6, 7). We now show that such LTP is greatly enhanced by longer stimulation periods...