Multi-modal characterization and simulation of human epileptic circuitry
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.
Additional InformationThe 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. Posted April 25, 2020. We wish to thank Allen Institute founder, Paul G. Allen, for his vision, encouragement, and support. We thank Brandon Blanchard and Kael Dai for assisting with illustrations, Soo Yeun Lee, Tom Chartrand, Yina Wei, Bosiljka Tasic for discussions, and Lynne Becker for transitional project management support. We thank the Allen Institute Tissue Procurement team, especially Nick Dee and Julie Nyhus, and Facilities team members for supporting human surgical tissue acquisition and transport. We are grateful to Caryl Tongco and Jae-Guen Yoon at Swedish Neuroscience Institute/Swedish Medical Center for coordinating patient consent, patient metadata, and tissue collections. We thank Dr. Carter Gerard for discussions and consultation early in the project, Dr. Ivan Soltesz for discussions and suggested analyses, and Drs. Rostad and Driscoll for providing de-identified patient tissue pathology reports. This research used resources of the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. We thank the Allen Institute for Brain Science and Paul G. Allen for the financial support. Author contributions: conceptualization: CAA, JT; data generation: AB, AN, RDF, PC, RM, BK, RG, SB, JT, RH; data curation: JB, CAA, JT, RDF, SMC, SS; formal analysis: AB, RDF and CAA; funding acquisition: CAA, JT, CK; investigation: AB, JT and CAA; project administration: CAA, JT, SMC, CK; writing original work: AB and CAA; writing – review and editing: all authors.
Submitted - 2020.04.24.060178v1.full.pdf
Supplemental Material - media-1.pdf
Supplemental Material - media-2.xlsx
Supplemental Material - media-3.xlsx