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Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2282-7. doi: 10.1073/pnas.1511513113. Epub 2016 Feb 8.

Territories of heterologous inputs onto Purkinje cell dendrites are segregated by mGluR1-dependent parallel fiber synapse elimination.

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Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan;
Department of Neurophysiology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan;
Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;


In Purkinje cells (PCs) of the cerebellum, a single "winner" climbing fiber (CF) monopolizes proximal dendrites, whereas hundreds of thousands of parallel fibers (PFs) innervate distal dendrites, and both CF and PF inputs innervate a narrow intermediate domain. It is unclear how this segregated CF and PF innervation is established on PC dendrites. Through reconstruction of dendritic innervation by serial electron microscopy, we show that from postnatal day 9-15 in mice, both CF and PF innervation territories vigorously expand because of an enlargement of the region of overlapping innervation. From postnatal day 15 onwards, segregation of these territories occurs with robust shortening of the overlapping proximal region. Thus, innervation territories by the heterologous inputs are refined during the early postnatal period. Intriguingly, this transition is arrested in mutant mice lacking the type 1 metabotropic glutamate receptor (mGluR1) or protein kinase Cγ (PKCγ), resulting in the persistence of an abnormally expanded overlapping region. This arrested territory refinement is rescued by lentivirus-mediated expression of mGluR1α into mGluR1-deficient PCs. At the proximal dendrite of rescued PCs, PF synapses are eliminated and free spines emerge instead, whereas the number and density of CF synapses are unchanged. Because the mGluR1-PKCγ signaling pathway is also essential for the late-phase of CF synapse elimination, this signaling pathway promotes the two key features of excitatory synaptic wiring in PCs, namely CF monoinnervation by eliminating redundant CF synapses from the soma, and segregated territories of CF and PF innervation by eliminating competing PF synapses from proximal dendrites.


Purkinje cell; cerebellum; climbing fiber; parallel fiber synapse elimination

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