Abstract
The Rho kinase (ROCK) signaling pathway is an attractive therapeutic target in neurodegenerationsince it has beenlinked to the prevention of neuronal death and neurite regeneration.The isoquinoline derivative fasudil is apotent ROCK inhibitor, which isalready approved for chronic clinical treatment in humans. However, theeffectsof chronic fasudil treatments on neuronal function are still unknown. We analyzedhere chronicfasudil treatment in primary rat hippocampal cultures. Neurons were stimulated with 20Hz field stimulation and we investigated pre-synaptic mechanisms and parameters regulating synaptic transmission after fasudil treatment by super resolution stimulated emission depletion (STED) microscopy, live-cell fluorescence imaging, and western blotting. Fasudil did not affectbasic synaptic function or the amount ofseveral synaptic proteins, but italtered the chronic dynamics of the synaptic vesicles. Fasudil reduced theproportion of the actively recycling vesicles, and shortened the vesiclelifetime, resulting overall in areduction of the synaptic response uponstimulation. We conclude that fasudil does not alter synapticstructure, acceleratesvesicle turnover, and decreases the number of released vesicles. This broadenstheknown spectrum of effects of this drug, and suggests new potential clinical uses.
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