Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming
- Carl von Ossietzky University of Oldenburg, Germany
- University of Iowa, United States
- Max Planck Florida Institute for Neuroscience, United States
- Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, Germany
- Max Planck Institute for Multidisciplinary Sciences, Germany
Abstract
Synapses contain a limited number of synaptic vesicles (SVs) that are released in response to action potentials (APs). Therefore, sustaining synaptic transmission over a wide range of AP firing rates and timescales depends on SV release and replenishment. Although actin dynamics impact synaptic transmission, how presynaptic regulators of actin signaling cascades control SV release and replenishment remains unresolved. Rac1, a Rho GTPase, regulates actin signaling cascades that control synaptogenesis, neuronal development, and postsynaptic function. However, the presynaptic role of Rac1 in regulating synaptic transmission is unclear. To unravel Rac1’s roles in controlling transmitter release, we performed selective presynaptic ablation of Rac1 at the mature mouse calyx of Held synapse. Loss of Rac1 increased synaptic strength, accelerated EPSC recovery after conditioning stimulus trains, and augmented spontaneous SV release with no change in presynaptic morphology or AZ ultrastructure. Analyses with constrained short-term plasticity models revealed faster SV priming kinetics and, depending on model assumptions, elevated SV release probability or higher abundance of tightly docked fusion-competent SVs in Rac1-deficient synapses. We conclude that presynaptic Rac1 is a key regulator of synaptic transmission and plasticity mainly by regulating the dynamics of SV priming and potentially SV release probability.
Data availability
All numerical data used to generate the figures are part of the respective source files. Experimental raw data and custom-written software central to the conclusion of this study are available at http://dx.doi.org/10.17632/c4b7gn8bh7 under the terms of the Creative Commons Attribution 4.0 License (CC BY 4.0).
Article and author information
Author details
Samuel M Young Jr.
Funding
National Institute on Deafness and Other Communication Disorders (R01 DC014093)
- Samuel M Young Jr.
National Institute of Neurological Disorders and Stroke (R01 NS110742)
- Samuel M Young Jr.
Deutsche Forschungsgemeinschaft (420075000)
- Christian Keine
Max Planck Institute for Multidisciplinary Sciences (open access funding)
- Mrinalini Ranjan
- Holger Taschenberger
Max Planck Florida Institute (open access funding)
- Connon I Thomas
- Naomi Kamasawa
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were performed following animal welfare laws and approved by the Institutional Committee for Care and Use of Animals at the University of Iowa (PHS Assurance No. D16-00009 (A3021-01) (Animal Protocol 0021952) and complied with accepted ethical best practices.
Copyright
© 2022, Keine et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming
eLife 11:e81505.
https://doi.org/10.7554/eLife.81505
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