Induction of cerebellar long-term depression (LTD) requires a postsynaptic cascade involving activation of mGluR1 and protein kinase C (PKC). Our understanding of this process has been limited by the fact that PKC is a large family of molecules, many isoforms of which are expressed in the relevant postsynaptic compartment, the cerebellar Purkinje cell. Here, we report that LTD is absent in Purkinje cells in which the α isoform of PKC has been reduced by targeted RNA interference or in cells derived from PKCα null mice. In both of these cases, LTD could be rescued by expression of PKCα but not other PKC isoforms. The special role of PKCα in cerebellar LTD is likely to derive from its unique PDZ ligand (QSAV). When this motif is mutated, PKCα no longer supports LTD. Conversely, when this PDZ ligand is inserted in a nonpermissive isoform, PKCγ, it confers the capacity for LTD induction.
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