Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network

Area of Science:

• Neuroscience
• Neurophysiology
• Computational Neuroscience

Background:

• Rhythmic epileptiform discharges are traditionally attributed to synaptic GABAergic connections within interneuronal networks.
• An alternative hypothesis suggests that synchronized interneuronal activity could elevate extracellular GABA, increasing tonic conductance via extrasynaptic receptors.

Purpose of the Study:

• To investigate the role of extracellular, volume-transmitted GABA in pacing rhythmic epileptiform discharges in the hippocampus.
• To elucidate the mechanisms by which extracellular GABA influences network rhythmicity.

Main Methods:

• Monitoring extracellular GABA levels using patch-clamp GABA "sniffers" and a novel optical GABA sensor in hippocampal slices.
• Employing neural network simulations incorporating volume-transmitted GABA signals.
• Performing simultaneous multi-neuron patch-clamp recordings and optogenetic stimulation of fast-spiking interneurons.
• Manipulating GABA uptake to alter extracellular GABA fluctuation dynamics.

Main Results:

• Periodic epileptiform discharges were preceded by transient, region-wide waves of extracellular GABA.
• Neural network simulations supported a cycle of GABA-driven inhibition and disinhibition.
• Reducing GABA uptake slowed rhythmic activity, demonstrating the impact of extracellular GABA dynamics.
• Synaptic GABAergic transmission and resting GABA levels remained unaffected by the GABA uptake manipulation.

Conclusions:

• Extrasynaptic, volume-transmitted GABA plays a crucial role in pacing regenerative rhythmic activity in brain networks.
• This study uncovers a novel mechanism for controlling network oscillations, with implications for understanding and treating epilepsy.