Induction of cerebellar long-term depression requires activation of calcineurin in Purkinje cells

Cerebellar long-term depression (LTD) is an activity-dependent depression of synaptic transmission from parallel fibers to Purkinje cells underlying certain forms of motor learning. LTD is induced by the conjunctive stimulation of parallel fibers and climbing fibers, both of which supply excitatory inputs to Purkinje cells. The conjunctive stimulation induces a large increase in intracellular Ca2+ concentration ([Ca2+]i) in Purkinje cells. Although the increase in [Ca2+]i is essential for LTD induction, the downstream signal transduction mechanism remains elusive. In this study, we show that LTD induction requires the activation of the Ca2+/calmodulin-dependent protein phosphatase 2B calcineurin. In acute cerebellar slices of mice, the LTD amplitude was significantly reduced in the presence of calcineurin inhibitors (cyclosporin A or FK506), whereas the basic electrophysiological properties of the parallel fiber-Purkinje cell synaptic transmission remained constant. Furthermore, a calcineurin autoinhibitory peptide perfused into Purkinje cells completely blocked LTD induction. On the other hand, microcystin LR, an inhibitor of protein phosphatase 1 and 2A, did not affect the induction of LTD. These results indicate that calcineurin activation is essential for LTD induction downstream of the conjunctive-stimulation-induced Ca2+ signal in Purkinje cells.