Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations
- University of Virginia, United States
- Massachusetts General Hospital, United States
- Harvard University, United States
- Princeton University, United States
- Stanford University School of Medicine, United States
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.
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/.
-
Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillationsDryad Digital Repository, doi:10.5061/dryad.4xgxd256f.
Article and author information
Author details
Christine Kyuyoung Lee
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.
Reviewing Editor
- Frances K Skinner, Krembil Research Institute, University Health Network, Canada
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.
Version history
- Received: June 1, 2020
- Accepted: September 8, 2020
- Accepted Manuscript published: September 9, 2020 (version 1)
- Version of Record published: October 1, 2020 (version 2)
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.
Metrics
-
- 1,481
- views
-
- 180
- downloads
-
- 6
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations
eLife 9:e59548.
https://doi.org/10.7554/eLife.59548
Further reading
-
- Computational and Systems Biology
- Genetics and Genomics
We propose a new framework for human genetic association studies: at each locus, a deep learning model (in this study, Sei) is used to calculate the functional genomic activity score for two haplotypes per individual. This score, defined as the Haplotype Function Score (HFS), replaces the original genotype in association studies. Applying the HFS framework to 14 complex traits in the UK Biobank, we identified 3619 independent HFS–trait associations with a significance of p < 5 × 10−8. Fine-mapping revealed 2699 causal associations, corresponding to a median increase of 63 causal findings per trait compared with single-nucleotide polymorphism (SNP)-based analysis. HFS-based enrichment analysis uncovered 727 pathway–trait associations and 153 tissue–trait associations with strong biological interpretability, including ‘circadian pathway-chronotype’ and ‘arachidonic acid-intelligence’. Lastly, we applied least absolute shrinkage and selection operator (LASSO) regression to integrate HFS prediction score with SNP-based polygenic risk scores, which showed an improvement of 16.1–39.8% in cross-ancestry polygenic prediction. We concluded that HFS is a promising strategy for understanding the genetic basis of human complex traits.
-
- Computational and Systems Biology
Revealing protein binding sites with other molecules, such as nucleic acids, peptides, or small ligands, sheds light on disease mechanism elucidation and novel drug design. With the explosive growth of proteins in sequence databases, how to accurately and efficiently identify these binding sites from sequences becomes essential. However, current methods mostly rely on expensive multiple sequence alignments or experimental protein structures, limiting their genome-scale applications. Besides, these methods haven’t fully explored the geometry of the protein structures. Here, we propose GPSite, a multi-task network for simultaneously predicting binding residues of DNA, RNA, peptide, protein, ATP, HEM, and metal ions on proteins. GPSite was trained on informative sequence embeddings and predicted structures from protein language models, while comprehensively extracting residual and relational geometric contexts in an end-to-end manner. Experiments demonstrate that GPSite substantially surpasses state-of-the-art sequence-based and structure-based approaches on various benchmark datasets, even when the structures are not well-predicted. The low computational cost of GPSite enables rapid genome-scale binding residue annotations for over 568,000 sequences, providing opportunities to unveil unexplored associations of binding sites with molecular functions, biological processes, and genetic variants. The GPSite webserver and annotation database can be freely accessed at https://bio-web1.nscc-gz.cn/app/GPSite.
