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Main Menu - Block
- Overview
- Anatomy and Histology
- Cell and Tissue Culture
- Cryo-Electron Microscopy
- Drosophila Resources
- Electron Microscopy
- Flow Cytometry Shared Resource (FCSR)
- Gene Targeting and Transgenics
- Janelia Experimental Technology
- Light Microscopy
- Media Prep
- Molecular Biology
- Project Pipeline Support
- Project Technical Resources
- Quantitative Genomics
- Scientific Computing Software
- Scientific Computing Systems
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- Vivarium
Abstract
Synchronised rhythmic activity of the brain is thought to arise from neuronal network behaviours that rely on synaptic signalling between individual cells. This notion has been a basis to explain periodic epileptiform discharges that are driven by interneuronal networks. However, interneuronal discharges not only engage cell-cell GABAergic transmission but also control the extracellular GABA concentration ([GABA]e) and thus tonic GABAA receptor conductance (Gtonic) across the cell population. At the same time, the firing activity of interneurons shows a bell-shaped dependence on Gtonic, suggesting an innate susceptibility to self-sustained oscillations. Here, we employ patch-clamp GABA ‘sniffer’ and fast two-photon excitation imaging of GABA sensor to show that periodic epileptiform discharges are preceded by a region-wide, rising wave of extracellular GABA. Neural network simulations based on such observations reveal that it is the volume-transmitted, extrasynaptic actions of GABA targeting multiple off-target cells that drives synchronised interneuronal spiking prompting periodic epileptiform bursts. We validate this hypothesis using simultaneous patch-clamp recordings from multiple nerve cells, selective optogenetic stimulation of fast-spiking interneurons, and by revealing the role of GABA uptake. Our findings thus unveil a key role of extrasynaptic, volume-transmitted GABA actions in enabling and pacing regenerative rhythmic activity in brain networks.
Previous bioRxiv PrePrint https://doi.org/10.1101/2021.03.25.437016
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