@article {68104, title = {Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network}, journal = {Current Biology}, volume = {33}, year = {2023}, month = {2023 Apr 10}, pages = {1249}, abstract = {

Mechanisms that entrain and drive rhythmic epileptiform discharges remain debated. Traditionally, this quest has been focusing on interneuronal networks driven by GABAergic connections that activate synaptic or extrasynaptic receptors. However, synchronised interneuronal discharges could also trigger a transient elevation of extracellular GABA across the tissue volume, thus raising tonic GABAA\ receptor conductance (Gtonic) in multiple cells. Here, we use patch-clamp GABA {\textquoteleft}sniffer{\textquoteright} and optical GABA sensor to show that periodic epileptiform discharges are preceded by region-wide, rising waves of extracellular GABA. Neural network simulations that incorporate volume-transmitted GABA signals point to mechanistic principles underpinning this relationship. We validate this hypothesis using simultaneous patch-clamp recordings from multiple nerve cells, selective optogenetic stimulation of fast-spiking interneurons. Critically, we manipulate GABA uptake to suppress extracellular GABA waves but not synaptic GABAergic transmission, which shows a clear effect on rhythm generation. Our findings thus unveil a key role of extrasynaptic, volume-transmitted GABA actions in pacing regenerative rhythmic activity in brain networks.

}, doi = {10.1016/j.cub.2023.02.051}, url = {https://doi.org/10.1016/j.cub.2023.02.051}, author = {Vincent Magloire and Leonid P. Savtchenko and Sergyi Sylantyev and Thomas P. Jensen and Nicholas Cole and Jonathan S. Marvin and Loren L. Looger and Dimitri M. Kullmann and Matthew C. Walker and Ivan Pavlov and Dmitri A. Rusakov} } @article {67704, title = {Extracellular glutamate and GABA transients at the transition from interictal spiking to seizures}, journal = {bioRxiv}, year = {2020}, month = {2020 Nov 15}, abstract = {

Focal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. Here we use fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes are accompanied by brief glutamate transients which are maximal at the initiation site and rapidly propagate centrifugally. GABA transients last longer than glutamate transients and are maximal ~1.5 mm from the focus where they propagate centripetally. At the transition to seizures, GABA transients are attenuated, whilst glutamate transients increase in spatial extent. The data imply that an annulus of feed-forward GABA release intermittently collapses, allowing seizures to escape from local inhibitory restraint.

}, doi = {10.1101/2020.11.13.381707}, author = {Yoshiteru Shimoda and Vincent Magloire and Jonathan S Marvin and Marco Leite and Loren L Looger and Dimitri M Kullmann} }