Motorneurons Require Cysteine String Protein-α to Maintain the Readily Releasable Vesicular Pool and Synaptic Vesicle Recycling

Abstract

Cysteine string protein-α (CSP-α) is a synaptic vesicle protein that prevents activity-dependent neurodegeneration by poorly understood mechanisms. We have studied the synaptic vesicle cycle at the motor nerve terminals of CSP-α knock-out mice expressing the synaptopHluorin transgene. Mutant nerve terminals fail to sustain prolonged release and the number of vesicles available to be released decreases. Strikingly, the SNARE protein SNAP-25 is dramatically reduced. In addition, endocytosis during the stimulus fails to maintain the size of the recycling synaptic vesicle pool during prolonged stimulation. Upon depolarization, the styryl dye FM 2-10 becomes trapped and poorly releasable. Consistently with the functional results, electron microscopy analysis revealed characteristic features of impaired synaptic vesicle recycling. The unexpected defect in vesicle recycling in CSP-α knock-out mice provides insights into understanding molecular mechanisms of degeneration in motor nerve terminals. Cysteine string protein-α (CSP-α) is a synaptic vesicle protein that prevents activity-dependent neurodegeneration. Rozas et al. have used synaptopHluorin imaging and electrophysiology to find alterations in synaptic vesicle priming and recycling at motor nerve terminals of CSP-α KO mice. © 2012 Elsevier Inc.This work has been supported by Spanish MINECO (Juan de la Cierva and FPU Programs, BES2008-002858, BFU2007-66008, BFU2010-15713, ERA-NET NEURON EUI2009-04084, CTQ2009-14431/BQU, SAF2010-20822-C02), Junta de Andalucía (P06-CVI-02392, P07-CVI-02854), Xunta de Galicia (INCITE09 209 084PR), HFSP (RGP 0045/2002-C and CDA0032/2005-C), Instituto de Salud Carlos III and FEDER.Peer Reviewe