The extreme C-terminus of GluRdelta2 is essential for induction of long-term depression in cerebellar slices.

Long-term depression (LTD) of parallel fibre (PF)-Purkinje cell synapses in the cerebellum is recognized as a cellular substrate of motor learning. Although the delta2 glutamate receptor (GluRdelta2) has been shown to be crucial for LTD, the mechanisms by which GluRdelta2 functions remain elusive. In this study, we developed a virus vector-based gene transfer approach to rescue impaired LTD in GluRdelta2-null Purkinje cells in cerebellar slice preparations. We demonstrated that LTD was restored in GluRdelta2-null Purkinje cells transduced with wild-type but not with mutant GluRdelta2, which lacked the PDZ-ligand domain in the C-terminus. Immunohistochemical analysis revealed no difference in expression levels or spine localization patterns between virally introduced wild-type and mutant GluRdelta2 proteins. Similarly, LTD was abrogated in Purkinje cells that had been acutely perfused with peptides, hampering the interaction of GluRdelta2 with PDZ proteins such as PSD-93, PTPMEG and S-SCAM but not with delphilin. Together, these results indicate that PDZ proteins that bind to the C-terminus of GluRdelta2 are not essential for localizing GluRdelta2 at synapses but are crucial for conveying signals necessary for the induction of LTD.