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The Hyperpolarization‐activated Cyclic Nucleotide‐gated 4 Channel as a Potential Anti‐seizure Drug Target by Qays Kharouf; A. Marie Phillips; Lauren E. Bleakley; Emma Morrisroe; Julia Oyrer; Linghan Jia; Andreas Ludwig; Liang Jin; Joseph A. Nicolazzo; Elisabetta Cerbai; M. Novella Romanelli; Steven Petrou; Christopher A. Reid is a Medicine article available to read on EtoBox.

What is The Hyperpolarization‐activated Cyclic Nucleotide‐gated 4 Channel as a Potential Anti‐seizure Drug Target about?

## Background and Purpose Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are encoded by four genes (HCN1–4) with distinct biophysical properties and functions within the brain. HCN4 channels activate slowly at robust hyperpolarizing potentials, making them more likely to be engaged during hyperexcitable neuronal network activity seen during seizures. HCN4 channels are also highly expressed in thalamic nuclei, a brain region implicated in seizure generalization. Here, we assessed the utility of targeting the HCN4 channel as an anti‐seizure strategy using pharmacological and genetic approaches. ## Experimental Approach The impact of reducing HCN4 channel function on seizure susceptibility and neuronal network excitability was studied using an HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model. ## Key Results EC18 (10 mg·kg^−1^) and brain‐specific HCN4 channel knockout reduced seizure susceptibility and proconvulsant‐mediated cortical spiking recorded using electrocorticography, with minimal effects on other mouse behaviours. EC18 (10 μM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18

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Author

Qays Kharouf; A. Marie Phillips; Lauren E. Bleakley; Emma Morrisroe; Julia Oyrer; Linghan Jia; Andreas Ludwig; Liang Jin; Joseph A. Nicolazzo; Elisabetta Cerbai; M. Novella Romanelli; Steven Petrou; Christopher A. Reid

Publisher

Nature Publishing Group; John Wiley and Sons; Springer Science and Business Media LLC; Wiley (Blackwell Publishing); Wiley-Blackwell; Society for Mining, Metallurgy and Exploration Inc.; Wiley; Research Square (ISSN 0007-1188)

Published

2020

Language

EN

Field

Medicine (Health Sciences)