Wong, Yan, Liu, Changliang, Wang, Shan Shan H, Roquas, Aram C F, Fowler, Stephen C and Kaeser, Pascal S (2018) Liprin-α3 controls vesicle docking and exocytosis at the active zone of hippocampal synapses. Proceedings of the National Academy of Sciences of the United States of America, 115 (9). pp. 2234-2239. ISSN 1091-6490

Abstract

The presynaptic active zone provides sites for vesicle docking and release at central nervous synapses and is essential for speed and accuracy of synaptic transmission. Liprin-α binds to several active zone proteins, and loss-of-function studies in invertebrates established important roles for Liprin-α in neurodevelopment and active zone assembly. However, Liprin-α localization and functions in vertebrates have remained unclear. We used stimulated emission depletion superresolution microscopy to systematically determine the localization of Liprin-α2 and Liprin-α3, the two predominant Liprin-α proteins in the vertebrate brain, relative to other active-zone proteins. Both proteins were widely distributed in hippocampal nerve terminals, and Liprin-α3, but not Liprin-α2, had a prominent component that colocalized with the active-zone proteins Bassoon, RIM, Munc13, RIM-BP, and ELKS. To assess Liprin-α3 functions, we generated Liprin-α3-KO mice by using CRISPR/Cas9 gene editing. We found reduced synaptic vesicle tethering and docking in hippocampal neurons of Liprin-α3-KO mice, and synaptic vesicle exocytosis was impaired. Liprin-α3 KO also led to mild alterations in active zone structure, accompanied by translocation of Liprin-α2 to active zones. These findings establish important roles for Liprin-α3 in active-zone assembly and function, and suggest that interplay between various Liprin-α proteins controls their active-zone localization.

Item Type:	Article
Date Deposited:	13 Apr 2018 00:45
Last Modified:	13 Apr 2018 00:45
URI:	https://oak.novartis.com/id/eprint/35923