Year: 2023
Type: article
Abstract: Mechanisms that entrain and pace rhythmic epileptiform discharges remain debated. Traditionally, the quest to understand them has focused on interneuronal networks driven by synaptic GABAergic connections. However, synchronized interneuronal discharges could also trigger the transient elevations of extracellular GABA across the tissue volume, thus raising tonic conductance ( G tonic ) of synaptic and extrasynaptic GABA receptors in multiple cells. Here, we monitor extracellular GABA in hippocampal slices using patch-clamp GABA "sniffer" and a novel optical GABA sensor, showing that periodic epileptiform discharges are preceded by transient, region-wide waves of extracellular GABA. Neural network simulations that incorporate volume-transmitted GABA signals point to a cycle of GABA-driven network inhibition and disinhibition underpinning this relationship. We test and validate this hypothesis using simultaneous patch-clamp recordings from multiple neurons and selective optogenetic stimulation of fast-spiking interneurons. Critically, reducing GABA uptake in order to decelerate extracellular GABA fluctuations—without affecting synaptic GABAergic transmission or resting GABA levels—slows down rhythmic activity. Our findings thus unveil a key role of extrasynaptic, volume-transmitted GABA in pacing regenerative rhythmic activity in brain networks.
Source: Current Biology
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $6,830
Funders: Howard Hughes Medical Institute, Wellcome Trust, Epilepsy Research UK, National Centre for the Replacement, Refinement and Reduction of Animals in Research, National Centre for the Replacement Refinement and Reduction of Animals in Research, Medical Research Council, European Research Council
Awards: Targeting Kir4.1 To Control Brain Excitability And Seizures, G1612526676, G1809651553, G2287368063, G2426410054, G2986170255, G3036229722, G315920569, G3757650242, Synaptic Neurology, G4706619419, G4942083293, Inhibitory brain dynamics for adaptive behaviour, A Network Approach to Gene Therapy for Refractory Epilepsies, G5789546139, Principles of synapse-astrocyte networking in the brain, Glutamate-gated chloride channel treatment of epilepsy, Neurotransmitter imaging to understand seizure mechanisms, Neural coding with the tripartite synapse., G778151877, G7860313503, Principles of synapse-astrocyte networking in the brain
OpenAlex ID: W4324354239