Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins

Cerebellar LTD requires activation of PKC and is expressed, at least in par t, as postsynaptic AMPA receptor internalization. Recently, it was shown th at AMPA receptor internalization requires clathrin-mediated endocytosis and depends upon the carboxy-terminal region of GluR2/3. Phosphorylation of Se r-880 in this region by PKC differentially regulates the binding of the PDZ domain-containing proteins GRIP/ABP and PICK1. Peptides, corresponding to the phosphorylated and dephosphorylated GluR2 carboxy-terminal PDZ binding motif, were perfused in cerebellar Purkinje cells grown in culture. Both th e dephospho form (which blocks binding of GRIP/ABP and PICK1) and the phosp ho form (which selectively blocks PICK1) attenuated LTD induction by glutam ate/depolarization pairing, as did antibodies directed against the PDZ doma in of PICK1. These findings indicate that expression of cerebellar LTD requ ires PKC-regulated interactions between the carboxy-terminal of GluR2/3 and PDZ domain-containing proteins.