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Region‐specific differences and areal interactions underlying transitions in epileptiform activity

Lookup NU author(s): Neela Codadu, Ryley Parrish, Professor Andrew Trevelyan

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Understanding the nature of epileptic state transitions remains a major goal for epilepsy research. Simple in vitro models offer unique experimental opportunities that we exploit to show that such transitions can arise from shifts in the ictal source of the activity. These transitions reflect the fact that cortical territories differ both in the type of epileptiform activity they can sustain and in their susceptibility to drug manipulation. In the zero-Mg2+ model, the earliest epileptiform activity is restricted to neocortical and entorhinal networks. Hippocampal bursting only starts much later, and triggers a marked transition in neo-/entorhinal cortical activity. Thereafter, the hippocampal activity acts as a pacemaker, entraining the other territories to their discharge pattern. This entrainment persists following transection of the major axonal pathways between hippocampus and cortex, indicating that it can be mediated through a non-synaptic route. Neuronal discharges are associated with large rises in extracellular [K+], but we show that these are very localized, and therefore are not the means of entraining distant cortical areas. We conclude instead that the entrainment occurs through weak field effects distant from the pacemaker, but which are highly effective at recruiting other brain territories that are already hyperexcitable. The hippocampal epileptiform activity appears unusually susceptible to drugs that impact on K+ conductances. These findings demonstrate that the local circuitry gives rise to stereotypical epileptic activity patterns, but these are also influenced by both synaptic and non-synaptic long-range effects. Our results have important implications for our understanding of epileptic propagation and anti-epileptic drug action.


Publication metadata

Author(s): Codadu NK, Parrish RR, Trevelyan AJ

Publication type: Article

Publication status: Published

Journal: The Journal of Physiology

Year: 2019

Volume: 597

Issue: 7

Pages: 2079-2096

Print publication date: 01/04/2019

Online publication date: 25/01/2019

Acceptance date: 23/01/2019

Date deposited: 14/02/2019

ISSN (print): 0022-3751

ISSN (electronic): 1469-7793

Publisher: Wiley

URL: https://doi.org/10.1113/JP277267

DOI: 10.1113/JP277267


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Funding

Funder referenceFunder name
P1504
MR/J013250/
MR/R005427/1Medical Research Council (MRC)

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