The Ins and Outs of GluD2-Why and How Purkinje Cells Use the Special Glutamate Receptor

The delta 2 glutamate receptor (GluD2) is predominantly expressed in cerebellar Purkinje cells and plays crucial roles in cerebellar functions. Indeed, the number of synapses between parallel fibers (PFs) and Purkinje cells is specifically and severely reduced in GluD2-null cerebellum. In addition, long-term depression (LTD) at PF-Purkinje cell synapses is impaired in these mice. Nevertheless, the mechanism by which GluD2 regulate these two functions-morphological and functional synaptic plasticity at PF synapses-has remained unclear. Recently, we found that Cbln1, a glycoprotein released from granule cells, was bound to the N-terminal domain of GluD2 and regulated formation and maintenance of PF-Purkinje cell synapses. Furthermore, we found that d-Ser released from Bergmann glia bound the ligand-binding domain of GluD2 and mediated LTD in a manner dependent on the C-terminus. These findings indicate how GluD2 is activated and regulates functions at PF-Purkinje cell synapses. A hypothesis about why GluD2 is employed by PF synapses is also discussed.