Regulation of Long-Term Depression and Climbing Fiber Territory by Glutamate Receptor δ2 at Parallel Fiber Synapses through its C-Terminal Domain in Cerebellar Purkinje Cells

Abstract

Glutamate receptor (GluR) delta2 selectively expressed in cerebellar Purkinje cells (PCs) plays key roles in long-term depression (LTD) induction at parallel fiber (PF)-PC synapses, motor learning, the matching and connection of PF-PC synapses in developing and adult cerebella, the elimination of multiple climbing fibers (CFs) during development, and the regulation of CF territory on PCs. However, it remains unsolved how GluRdelta2 regulates cerebellar synaptic plasticity, PF-PC synapse formation, and CF wiring. One possible signaling mechanism through GluRdelta2 is signaling by protein-protein interactions. The C-terminal region of GluRdelta2 contains at least three domains for protein-protein interactions. The PDZ (postsynaptic density-95/Discs large/zona occludens 1)-binding domain at the C terminal, named as the T site, interacts with several postsynaptic density proteins. Here, we generated GluRdelta2DeltaT mice carrying mutant GluRdelta2 lacking the T site. There were no significant differences in the amount of receptor proteins at synapses, histological features, and the fine structures of PF-PC synapses between wild-type and GluRdelta2DeltaT mice. However, LTD induction at PF-PC synapses and improvement in the accelerating rotarod test were impaired in GluRdelta2DeltaT mice. Furthermore, CF territory expanded distally and ectopic innervation of CFs occurred at distal dendrites in GluRdelta2DeltaT mice, but the elimination of surplus CF innervation at proximal dendrites appeared to proceed normally. These results suggest that the C-terminal T site of GluRdelta2 is essential for LTD induction and the regulation of CF territory but is dispensable for PF-PC synapse formation and the elimination of surplus CFs at proximal dendrites during development.