NEW (BUT OLD) MOLECULES REGULATING SYNAPSE INTEGRITY AND PLASTICITY: Cbln1 AND THE δ2 GLUTAMATE RECEPTOR

The delta 2 glutamate receptor (GluR delta 2) is predominantly expressed in cerebellar Purkinje cells and plays crucial roles in cerebellar functions: GluR delta 2-null mice display ataxia and impaired motor learning. Interestingly, the contact state of synapses between parallel fibers (PFs) and Purkinje cells is specifically and severely affected, and the number of normal PF synapses is markedly reduced in GluR delta 2-null Purkinje cells. Furthermore, long-term depression at PF-Purkinje cell synapses is abrogated. Cbln1, a member of the C1q/tumor necrosis factor (TNF) superfamily, is predominantly expressed and released from cerebellar granule cells. Unexpectedly, the behavioral, physiological and anatomical phenotypes of cbln1-null mice precisely mimic those of GluR delta 2-null mice. Thus, we propose that Cbln1, which is released from granule cells, and GluR delta 2, which is predominantly expressed in Purkinje cells, are involved in a common signaling pathway crucial for synapse formation/maintenance and plasticity in the cerebellum. Since molecules related to Cbln1 are expressed in various brain regions other than the cerebellum, other C1q/TNF superfamily proteins may also regulate various aspects of synapses in the CNS. Therefore, an understanding of the signaling mechanisms underlying Cbln1 and GluR delta 2 in the cerebellum will provide new insights into the roles of C1q/TNF superfamily proteins as new cytokines that regulate normal and abnormal brain functions. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.