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Rho‐kinase inhibition by fasudil modulates pre‐synaptic vesicle dynamics
Author(s) -
Saal Kim Ann,
Warth Pérez Arias Carmina,
Roser AnnaElisa,
Christoph Koch Jan,
Bähr Mathias,
Rizzoli Silvio O.,
Lingor Paul
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15274
Subject(s) - fasudil , synaptic vesicle , neurotransmission , rho associated protein kinase , stimulation , chemistry , rho kinase inhibitor , neuroscience , microbiology and biotechnology , synaptic augmentation , neurite , pharmacology , vesicle , biology , biochemistry , signal transduction , receptor , membrane , in vitro
The Rho kinase (ROCK) signaling pathway is an attractive therapeutic target in neurodegeneration since it has been linked to the prevention of neuronal death and neurite regeneration. The isoquinoline derivative fasudil is a potent ROCK inhibitor, which is already approved for chronic clinical treatment in humans. However, the effects of chronic fasudil treatments on neuronal function are still unknown. We analyzed here chronic fasudil treatment in primary rat hippocampal cultures. Neurons were stimulated with 20 Hz 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 affect basic synaptic function or the amount of several synaptic proteins, but it altered the chronic dynamics of the synaptic vesicles. Fasudil reduced the proportion of the actively recycling vesicles, and shortened the vesicle lifetime, resulting overall in a reduction of the synaptic response upon stimulation. We conclude that fasudil does not alter synaptic structure, accelerates vesicle turnover, and decreases the number of released vesicles. This broadens the known spectrum of effects of this drug, and suggests new potential clinical uses.