The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

Autor:	Andreas Ludwig, Lauren E Bleakley, Christopher A. Reid, Liang Jin, Linghan Jia, Emma Morrisroe, Steven Petrou, Joseph A. Nicolazzo, Qays Kharouf, A. Marie Phillips, Julia Oyrer, M. Novella Romanelli, Elisabetta Cerbai
Rok vydání:	2020
Předmět:	0301 basic medicine Central nervous system Cyclic Nucleotide-Gated Cation Channels Biology Mice 03 medical and health sciences Bursting Epilepsy 0302 clinical medicine Seizures Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Biological neural network medicine Animals Electrocorticography Ion channel Pharmacology medicine.diagnostic_test Hyperpolarization (biology) medicine.disease Research Papers 030104 developmental biology medicine.anatomical_structure Pharmaceutical Preparations Knockout mouse Nucleotides Cyclic Neuroscience 030217 neurology & neurosurgery
Zdroj:	Br J Pharmacol
ISSN:	1476-5381 0007-1188
DOI:	10.1111/bph.15088
Popis:	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 generalisation. 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 a HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model. KEY RESULTS: EC18 (10mg 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 (10μM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18 was not protective against proconvulsant-mediated seizures in the conditional HCN4 channel knockout mouse and did not reduce bursting behaviour in AAV-HCN4 shRNA infected mouse cortical cultures. CONCLUSIONS AND IMPLICATIONS: These data suggest the HCN4 channel as a potential pharmacologically relevant target for anti-seizure drugs that is likely to have a low side-effect liability in the central nervous system.
Databáze:	OpenAIRE
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