Role of the internal Shank-binding segment of glutamate receptor δ2 in synaptic localization and cerebellar functions

Glutamate receptor (GluR) δ2 selectively expressed in cerebellar Purkinje cells (PCs) plays key roles in cerebellar long-term depression (LTD), motor learning and formation of parallel fiber (PF)-PC synapses. We have recently shown that the PDZ [postsynaptic density (PSD)-95/Discs large/zona occludens-1]-binding domain at the C-terminal, the T site, is essential for LTD induction and the regulation of climbing fiber (CF) territory, but is dispensable for synaptic localization of GluRδ2, PF-PC synapse formation and CF elimination process. To investigate the functional roles of the S segment, the second PDZ-binding domain in the middle of the C-terminal cytoplasmic region, we generated GluRδ2ΔS mice carrying mutant GluRδ2 lacking this segment. The amount of GluRδ2ΔS in mutant mice was reduced compared with that of GluRδ2 in wild-type mice. However, the extent of decrease was much larger in the PSD fractions than in cerebellar homogenates, suggesting the requirement of the S segment for efficient synaptic localization. Furthermore, mismatched PF synapses and free spines emerged and CF-innervation territory on PC dendrites expanded in GluRδ2ΔS mice. On the other hand, the performance in the rotarod test was comparable between wild-type and GluRδ2ΔS mice. These results suggest that the S segment and T site, the two PDZ-binding domains in the C-terminal cytoplasmic region, are differentially involved in diverse GluRδ2 functions.