Moleculare Mechanisms of Synapse Elimination and Stabilization in Developing Brain

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(1) Postnatal development of cerebellar climbing fiber synaptic response :Electrophysiological investugation was performed to follow the developmental change of cerebellar climbing fiber (CF) to Purkinje cell (PC) synaptic responses in mice. Percentage of PCs innervated by multiple CFs decreased markedly during the first two postnatal weeks. Climbing fiber responses during the first postnatal week had slower rise times and exhibited greaterer extent of paired-pulse depression than those of mature animals. We have demonstrated in the rat that paired-pulse depression is mainly due to decreased transmitter release from CF presynaptic terminals.(2) Analyzes of mGluR1, Galphaq and PLCbeta4 delicient mice :The type 1 metabotropic glutamate receptor (mGluR1) is considered to activate in PCs protein kinase Cgamma (PKCgamma) through Gq type heterotrimeric G protein and phospholipase C beta4 (PLCbeta4). We examined the development of CF synapses in three strains of mutant mice lacking mGluR1, the alpha subunit of Gq (Galphaq) and PLCbeta4, respectively. These three strains of mutant mice have persistent multiple CF innervation of PCs due to the defect during the third postnatal week, which is similar to the phenotype of previously reported PKCgamma mutant mice. These results suggest that signal transduction cascade that involves mGluR1, Gq, PLCbeta4 and PKCgamma is crucial for CF synapse elimination during the third postnatal week.(3) Analyzes of GluRdelta2 deficient mice :We analyzed cerebellar parallel fiber (PF) and CF synapse formation in mutant mice lacking the glutamate receptor delta2 (GluRdelta2), the PC specific ionotropic GluR.By using electron microscopic and electrophysiological methods, we demonstrated that the density of PF to PC synapses in the GluRdelta2 mutant was less than half of that of the wild type. In addition, we found that CFs formed ectopic synapses onto distal dendrites of PCs, which is presumably due to impaired PF to PC synapse formation.