Multiple Phases of Climbing Fiber Synapse Elimination in the Developing Cerebellum

Cbln1 is a cerebellum-specific protein of previously unknown function that is structurally related to the C1q and tumor necrosis factor families of proteins. We show that Cbln1 is a glycoprotein secreted from cerebellar granule cells that is essential for three processes in cerebellar Purkinje cells: the matching and maintenance of pre- and postsynaptic elements at parallel fiber-Purkinje cell synapses, the establishment of the proper pattern of climbing fiber-Purkinje cell innervation, and induction of long-term depression at parallel fiber-Purkinje cell synapses. Notably, the phenotype of cbln1-null mice mimics loss-of-function mutations in the orphan glutamate receptor, GluR delta2, a gene selectively expressed in Purkinje neurons. Therefore, Cbln1 secreted from presynaptic granule cells may be a component of a transneuronal signaling pathway that controls synaptic structure and plasticity.

The speed of clearance of transmitter from the cleft influences many aspects of synaptic function, including the timecourse of the postsynaptic response and the peak postsynaptic receptor occupancy. The timecourse of transmitter clearance can be estimated either by detailed theoretical modelling, or from the attenuation of synaptic transmission produced by a low-affinity competitive antagonist. These approaches have been applied to several classes of central synapse, and results obtained are in broad agreement. The average concentration of transmitter peaks in the range 1-5 mM, and clearance is biphasic, with time constants of approximately 100 microseconds and 2 ms. The pulse of transmitter, although very brief, can prolong the timecourse of the fastest AMPA synaptic currents, and is sufficient to saturate postsynaptic GABA, glycine or NMDA receptors.