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Activity clamp provides insights into paradoxical effects of the anti-seizure drug carbamazepine

Morris, G; Leite, M; Kullmann, DM; Pavlov, I; Schorge, S; Lignani, G; (2017) Activity clamp provides insights into paradoxical effects of the anti-seizure drug carbamazepine. The Journal of Neuroscience , 37 (22) pp. 5484-5495. 10.1523/JNEUROSCI.3697-16.2017. Green open access

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Abstract

A major challenge in experimental epilepsy research is to reconcile the effects of anti-epileptic drugs (AEDs) on individual neurons with their network-level actions. Highlighting this difficulty, it is unclear why carbamazepine (CBZ), a front-line AED with a known molecular mechanism, has been reported to increase epileptiform activity in several clinical and experimental studies. We confirmed in an in vitro mouse model (both sexes) that the frequency of interictal bursts increased following CBZ perfusion. To address the underlying mechanisms we developed a method, activity clamp, to distinguish the response of individual neurons from network-level actions of CBZ. We first recorded barrages of synaptic conductances from neurons during epileptiform activity, and then replayed them in pharmacologically isolated neurons under control conditions and in the presence of CBZ. CBZ consistently decreased the reliability of the second action potential in each burst of activity. Conventional current clamp recordings using excitatory ramp or square step current injections failed to reveal this effect. Network modelling showed that a CBZ-induced decrease of neuron recruitment during epileptic bursts can lead to an increase in burst frequency at the network level, by reducing the refractoriness of excitatory transmission. By combining activity clamp with computer simulations, the present study provides a potential explanation for the paradoxical effects of CBZ on epileptiform activity.SIGNIFICANCE STATEMENTThe effects of anti-epileptic drugs on individual neurons are difficult to separate from their network-level actions. Although carbamazepine has a known anti-epileptic mechanism, it has also been reported to paradoxically increase epileptiform activity in clinical and experimental studies. To investigate this paradox during realistic neuronal epileptiform activity we developed a method, activity clamp, to distinguish effects of carbamazepine on individual neurons from network-level actions. We demonstrate that carbamazepine consistently decreases the reliability of the second action potential in each burst of epileptiform activity. Network modelling shows that this effect on individual neuronal responses could explain the paradoxical effect of carbamazepine at the network level.

Type: Article
Title: Activity clamp provides insights into paradoxical effects of the anti-seizure drug carbamazepine
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.3697-16.2017
Publisher version: http://doi.org/10.1523/JNEUROSCI.3697-16.2017
Language: English
Additional information: Copyright © 2017 Leite1. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1556535
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