Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations

Abstract
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Abstract

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 GABA_B 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 GABA_B receptor activity promote channel opening and intensify oscillations. These results have implications for therapeutics that modulate inhibition kinetics.

Data availability

Source data files have been provided for Figures 1-5, 8-9. Oscillations data, dynamic clamp data are available via Dryad (https://doi.org/10.5061/dryad.4xgxd256f). All code for reproducing results are available online at https://github.com/luadam4c/m3ha_published/.

The following data sets were generated

(2020) Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations
Dryad Digital Repository, doi:10.5061/dryad.4xgxd256f.

https://datadryad.org/stash/share/4vB7IQTQTZq-Mb4ZKbXGYUz-gtkfnsVTKe7uJz4pde4

Article and author information

Author details

Adam C Lu

Department of Pharmacology, University of Virginia, Charlottesville, United States

For correspondence
al4ng@virginia.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-1008-1057
Christine Kyuyoung Lee

Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-1422-4606
Max Kleiman-Weiner

Department of Psychology, Harvard University, Cambridge, MA, United States

Competing interests
No competing interests declared.
Brian Truong

Department of Pharmacology, University of Virginia, Charlottesville, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-0179-0932
Megan Wang

Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-8845-4936
John Huguenard

Neurology and Neurological Sciences, Neurosurgery, Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States

For correspondence
John.Huguenard@stanford.edu

Competing interests
John Huguenard, Senior editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-6950-1191
Mark P Beenhakker

Department of Pharmacology, University of Virginia, Charlottesville, United States

For correspondence
mpb5y@virginia.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-4541-0201

Funding

National Institute of Neurological Disorders and Stroke (NIH grant R01-NS099586)

Adam C Lu
Brian Truong
Mark P Beenhakker

National Institute of Neurological Disorders and Stroke (NIH grant R01-NS034774)

Christine Kyuyoung Lee
Max Kleiman-Weiner
Megan Wang
John Huguenard

University of Virginia (Whitfield-Randolph Scholarship)

Adam C Lu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

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.

Copyright

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.