[Synapse elimination and functional neural circuit formation in the cerebellum]

Neuronal connections are initially redundant, but unnecessary connections are eliminated subsequently during postnatal development. This process, known as 'synapse elimination', is thought to be crucial for establishing functionally mature neural circuits. The climbing fiber (CF) to the Purkinje cell (PC) synapse in the cerebellum is a representative model of synapse elimination. We disclose that one-to-one connection from CF to PC is established through four distinct phases: (1) strengthening of a single CF among multiple CFs in each PC at P3-P7, (2) translocation of a single strengthened CF to PC dendrites from around P9, and (3) early phase (P7 to around P11) and (4) late phase (around P12 to P17) of elimination of weak CF synapses from PC somata. Mice with PC-selective deletion of P/Q-type voltage-dependent Ca2+ channel (VDCC) exhibit severe defects in strengthening of single CFs, dendritic translocation of single CFs and CF elimination from P7. In contrast, mice with a mutation of a single allele for the GABA-synthesizing enzyme GAD67 have a selective impairment of CF elimination from P10 due to reduced inhibition and elevated Ca2+ influx to PC somata. Thus, regulation of Ca2+ influx to PCs is crucial for the four phases of CF synapse elimination.