A new role of kainate receptors as synaptic organizers for climbing fiber-Purkinje cell synapses in the cerebellum

Purkinje cells (PCs) are known to express both GluK1 and GluK4 kainate receptor (KAR) subunits, but the exact role of KARs in synaptic information transfer to PCs is unknown. In this study, we discovered that climbing fiber (CF) to PC synapses contain heteromeric GluK1/GluK4 synaptic KARs. Genetic deletion of Grik4, which encodes for GluK4 subunits, resulted in the lack of synaptic but not extrasynaptic KARs, while deletion of Grik1 (GluK1 subunits) eliminated both synaptic and extrasynaptic KARs. Surprisingly, the absence of synaptic KARs led to a significant reduction in the EPSC component mediated by AMPA receptors at CF-PC synapses, but not at parallel fiber (PF) to PC synapses. This anti-homeostatic plasticity impaired long-term depression and resulted in motor learning deficits. To understand the mechanism by which this occurred, we discovered that GluK4 KO mice had a lower number of CF-PC synapses, which extended over a retracted territory along PC dendrites. This was similar to the results observed when C1qL1 protein, recently identified as a new class of synaptic organizers, or its postsynaptic receptor Bai3 were genetically removed. Further investigation revealed that GluK4 was required for C1qL1 to go to the synapse and that GluK4 coupled with C1qL1/Bai3 stabilize each other at the CF-PC synapse making possible synaptogenesis, maturation and maintenance of synapses between the CF and the PC. These findings unveil a unique and unexpected role for KARs as synaptic scaffolds, orchestrating synapses by forming a C1ql1-KAR-Bai3 complex in the cerebellum and likely in other synapses.