Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination

Liang Zhou, Dong Yang, De-Juan Wang, Ya-Jun Xie, Jia-Huan Zhou, Lin Zhou, Hao Huang, Shuo Han, Chong-Yu Shao, Hua-Shun Li, J Julius Zhu, Meng-Sheng Qiu, Chris I De Zeeuw, Ying Shen

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Abstract

Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber-PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1.

Original languageEnglish
Pages (from-to)15474-9
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number50
DOIs
Publication statusPublished - 15 Dec 2015

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