Absence seizures result from 3-5 Hz generalized thalamocortical oscillations that depend on highly regulated inhibitory neurotransmission in the thalamus. Efficient reuptake of the inhibitory neurotransmitter GABA is essential, and reuptake failure worsens human seizures. Here, we show that blocking GABA transporters (GATs) in acute rat brain slices containing key parts of the thalamocortical seizure network modulates epileptiform activity. As expected, we found that blocking either GAT1 or GAT3 prolonged oscillations. However, blocking both GATs unexpectedly suppressed oscillations. Integrating experimental observations into single-neuron and network-level computational models shows how a non-linear dependence of T-type calcium channel gating on GABAB receptor activity regulates network oscillations. Receptor activity that is either too brief or too protracted fails to sufficiently open T-type channels necessary for sustaining oscillations. Only within a narrow range does prolonging GABAB receptor activity promote channel opening and intensify oscillations. These results have implications for therapeutics that modulate inhibition kinetics.
- Adam C Lu
- Brian Truong
- Mark P Beenhakker
- Christine Kyuyoung Lee
- Max Kleiman-Weiner
- Megan Wang
- John Huguenard
- Adam C Lu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Oscillation experiments were performed in accordance with Protocol #3892 approved by the Institutional Animal Care and Use Committee at the University of Virginia. Dynamic clamp experiments were performed in accordance with protocols approved by the Administrative Panel on Laboratory Animal Care at Stanford University. Rats were deeply anesthetized with pentobarbital before transcardial perfusion, and every effort was made to minimize suffering.
- Frances K Skinner, Krembil Research Institute, University Health Network, Canada
- Received: June 1, 2020
- Accepted: September 8, 2020
- Accepted Manuscript published: September 9, 2020 (version 1)
© 2020, Lu 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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