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Multi-modal characterization and simulation of human epileptic circuitry

View ORCID ProfileAnatoly Buchin, View ORCID ProfileRebecca de Frates, View ORCID ProfileAnirban Nandi, View ORCID ProfileRusty Mann, View ORCID ProfilePeter Chong, View ORCID ProfileLindsay Ng, View ORCID ProfileJeremy Miller, View ORCID ProfileRebecca Hodge, View ORCID ProfileBrian Kalmbach, Soumita Bose, View ORCID ProfileUeli Rutishauser, Stephen McConoughey, Ed Lein, View ORCID ProfileJim Berg, View ORCID ProfileStaci Sorensen, View ORCID ProfileRyder Gwinn, View ORCID ProfileChristof Koch, View ORCID ProfileJonathan Ting, View ORCID ProfileCostas A. Anastassiou
doi: https://doi.org/10.1101/2020.04.24.060178
Anatoly Buchin
1Allen Institute for Brain Science, Seattle, WA, USA
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  • For correspondence: costasa@alleninstitute.org costas.anastassiou@gmail.com anatolyb@alleninstitute.org
Rebecca de Frates
1Allen Institute for Brain Science, Seattle, WA, USA
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Anirban Nandi
1Allen Institute for Brain Science, Seattle, WA, USA
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Rusty Mann
1Allen Institute for Brain Science, Seattle, WA, USA
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Peter Chong
1Allen Institute for Brain Science, Seattle, WA, USA
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Lindsay Ng
1Allen Institute for Brain Science, Seattle, WA, USA
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Jeremy Miller
1Allen Institute for Brain Science, Seattle, WA, USA
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Rebecca Hodge
1Allen Institute for Brain Science, Seattle, WA, USA
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Brian Kalmbach
1Allen Institute for Brain Science, Seattle, WA, USA
2University of Washington, Seattle, USA
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Soumita Bose
1Allen Institute for Brain Science, Seattle, WA, USA
3CiperHealth, San Francisco, USA
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Ueli Rutishauser
4Cedars-Sinai Medical Center, Los Angeles CA, USA
5California Institute of Technology, Pasadena, CA, USA
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Stephen McConoughey
1Allen Institute for Brain Science, Seattle, WA, USA
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Ed Lein
1Allen Institute for Brain Science, Seattle, WA, USA
7University of Washington, Seattle, WA, USA
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Jim Berg
1Allen Institute for Brain Science, Seattle, WA, USA
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Staci Sorensen
1Allen Institute for Brain Science, Seattle, WA, USA
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Ryder Gwinn
6Swedish Medical Center, Seattle, WA, USA
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Christof Koch
1Allen Institute for Brain Science, Seattle, WA, USA
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Jonathan Ting
1Allen Institute for Brain Science, Seattle, WA, USA
7University of Washington, Seattle, WA, USA
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Costas A. Anastassiou
1Allen Institute for Brain Science, Seattle, WA, USA
8University of British Columbia, Vancouver, BC, CA
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  • ORCID record for Costas A. Anastassiou
  • For correspondence: costasa@alleninstitute.org costas.anastassiou@gmail.com anatolyb@alleninstitute.org
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Abstract

Temporal lobe epilepsy is the fourth most common neurological disorder with about 40% of patients not responding to pharmacological treatment. Increased cellular loss in the hippocampus is linked to disease severity and pathological phenotypes such as heightened seizure propensity. While the hippocampus is the target of therapeutic interventions such as temporal lobe resection, the impact of the disease at the cellular level remains unclear in humans. Here we show that properties of hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from epilepsy patients. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume, surface area and spine density. Single-cell RNA sequencing combined with simulations ascribe the observed electrophysiological changes to gradual modification in three key ion channel conductances: BK, Cav2.2 and Kir2.1. In a bio-realistic computational network model, we show that the changes related to disease progression bring the circuit into a more excitable state. In turn, we observe that by reversing these changes in the three key conductances produces a less excitable, “early disease-like” state. These results provide mechanistic understanding of epilepsy in humans and will inform future therapies such as viral gene delivery to reverse the course of the disorder.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 05, 2020.
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Multi-modal characterization and simulation of human epileptic circuitry
Anatoly Buchin, Rebecca de Frates, Anirban Nandi, Rusty Mann, Peter Chong, Lindsay Ng, Jeremy Miller, Rebecca Hodge, Brian Kalmbach, Soumita Bose, Ueli Rutishauser, Stephen McConoughey, Ed Lein, Jim Berg, Staci Sorensen, Ryder Gwinn, Christof Koch, Jonathan Ting, Costas A. Anastassiou
bioRxiv 2020.04.24.060178; doi: https://doi.org/10.1101/2020.04.24.060178
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Multi-modal characterization and simulation of human epileptic circuitry
Anatoly Buchin, Rebecca de Frates, Anirban Nandi, Rusty Mann, Peter Chong, Lindsay Ng, Jeremy Miller, Rebecca Hodge, Brian Kalmbach, Soumita Bose, Ueli Rutishauser, Stephen McConoughey, Ed Lein, Jim Berg, Staci Sorensen, Ryder Gwinn, Christof Koch, Jonathan Ting, Costas A. Anastassiou
bioRxiv 2020.04.24.060178; doi: https://doi.org/10.1101/2020.04.24.060178

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