1. Computational and Systems Biology
  2. Neuroscience
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Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations

  1. Adam C Lu  Is a corresponding author
  2. Christine Kyuyoung Lee
  3. Max Kleiman-Weiner
  4. Brian Truong
  5. Megan Wang
  6. John Huguenard  Is a corresponding author
  7. Mark P Beenhakker  Is a corresponding author
  1. University of Virginia, United States
  2. Massachusetts General Hospital, United States
  3. Harvard University, United States
  4. Princeton University, United States
  5. Stanford University School of Medicine, United States
Research Article
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Cite this article as: eLife 2020;9:e59548 doi: 10.7554/eLife.59548

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 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.

Article and author information

Author details

  1. Adam C Lu

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    For correspondence
    al4ng@virginia.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1008-1057
  2. Christine Kyuyoung Lee

    Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1422-4606
  3. Max Kleiman-Weiner

    Department of Psychology, Harvard University, Cambridge, MA, United States
    Competing interests
    No competing interests declared.
  4. Brian Truong

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0179-0932
  5. Megan Wang

    Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8845-4936
  6. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6950-1191
  7. Mark P Beenhakker

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    For correspondence
    mpb5y@virginia.edu
    Competing interests
    No competing interests declared.
    ORCID icon "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.

Reviewing Editor

  1. Frances K Skinner, Krembil Research Institute, University Health Network, Canada

Publication history

  1. Received: June 1, 2020
  2. Accepted: September 8, 2020
  3. Accepted Manuscript published: September 9, 2020 (version 1)

Copyright

© 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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