Loss of neuronal heterogeneity in epileptogenic human tissue impairs network resilience to sudden changes in synchrony

Scott Rich; Homeira Moradi Chameh; Jeremie Lefebvre; Taufik A Valiante

doi:10.1016/j.celrep.2022.110863

Loss of neuronal heterogeneity in epileptogenic human tissue impairs network resilience to sudden changes in synchrony

Cell Rep. 2022 May 24;39(8):110863. doi: 10.1016/j.celrep.2022.110863.

Authors

Scott Rich¹, Homeira Moradi Chameh¹, Jeremie Lefebvre², Taufik A Valiante³

Affiliations

¹ Division of Clinical and Computational Neuroscience, Krembil Brain Institute, Toronto, ON M5T 1M8, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), University of Toronto, Toronto, ON M5S 1A1, Canada.
² Division of Clinical and Computational Neuroscience, Krembil Brain Institute, Toronto, ON M5T 1M8, Canada; Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada; Department of Mathematics, University of Toronto, Toronto, ON M5S 1A1, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), University of Toronto, Toronto, ON M5S 1A1, Canada. Electronic address: jeremie.lefebvre@uottawa.ca.
³ Division of Clinical and Computational Neuroscience, Krembil Brain Institute, Toronto, ON M5T 1M8, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 1A1, Canada; Electrical and Computer Engineering, University of Toronto, Toronto, ON M5S 1A1, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada; Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A1, Canada; Max Planck-University of Toronto Centre for Neural Science and Technology, University of Toronto, Toronto, ON M5S 1A1, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), University of Toronto, Toronto, ON M5S 1A1, Canada. Electronic address: taufik.valiante@uhn.ca.

PMID: 35613586
DOI: 10.1016/j.celrep.2022.110863

Abstract

A myriad of pathological changes associated with epilepsy can be recast as decreases in cell and circuit heterogeneity. We thus propose recontextualizing epileptogenesis as a process where reduction in cellular heterogeneity, in part, renders neural circuits less resilient to seizure. By comparing patch clamp recordings from human layer 5 (L5) cortical pyramidal neurons from epileptogenic and non-epileptogenic tissue, we demonstrate significantly decreased biophysical heterogeneity in seizure-generating areas. Implemented computationally, this renders model neural circuits prone to sudden transitions into synchronous states with increased firing activity, paralleling ictogenesis. This computational work also explains the surprising finding of significantly decreased excitability in the population-activation functions of neurons from epileptogenic tissue. Finally, mathematical analyses reveal a bifurcation structure arising only with low heterogeneity and associated with seizure-like dynamics. Taken together, this work provides experimental, computational, and mathematical support for the theory that ictogenic dynamics accompany a reduction in biophysical heterogeneity.

Keywords: CP: Neuroscience; computational neuroscience; epilepsy; human; neuronal electrophysiology; neuronal heterogeneity; seizure.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Epilepsy*
Humans
Neurons* / physiology
Pyramidal Cells / physiology
Seizures