Format

Send to

Choose Destination
J Neurosci. 2018 Jul 25;38(30):6615-6627. doi: 10.1523/JNEUROSCI.0896-17.2018. Epub 2018 Jun 20.

Suppression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function in Thalamocortical Neurons Prevents Genetically Determined and Pharmacologically Induced Absence Seizures.

Author information

1
Neuroscience Division, School of Biosciences, Cardiff University, Cardiff CF10 3AX, United Kingdom, francois.david@inserm.fr Crunelli@cardiff.ac.uk.
2
Lyon Neuroscience Research Center, CNRS UMR 5292-INSERM U1028-Université Claude Bernard, 69008 Lyon, France.
3
Neuroscience Division, School of Biosciences, Cardiff University, Cardiff CF10 3AX, United Kingdom.
4
Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.
5
Department of Physiology, Anatomy, and Neuroscience, University of Szeged, Szeged 6726, Hungary.
6
Department of Pharmacology and Clinical 34452 Pharmacology, Marmara University School of Medicine, Istanbul 81326, Turkey.
7
Department of Physiology and Biochemistry, University of Malta, Msida MSD 2080, Malta, and.
8
Department of Physiology, Feinberg School of Medicine, Northwestern University, Robert H Lurie Medical Research Center, Chicago, Illinois 60611.

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the Ih current they generate contribute to the pathophysiological mechanisms of absence seizures (ASs), but their precise role in neocortical and thalamic neuronal populations, the main components of the network underlying AS generation, remains controversial. In diverse genetic AS models, Ih amplitude is smaller in neocortical neurons and either larger or unchanged in thalamocortical (TC) neurons compared with nonepileptic strains. A lower expression of neocortical HCN subtype 1 channels is present in genetic AS-prone rats, and HCN subtype 2 knock-out mice exhibit ASs. Furthermore, whereas many studies have characterized Ih contribution to "absence-like" paroxysmal activity in vitro, no data are available on the specific role of cortical and thalamic HCN channels in behavioral seizures. Here, we show that the pharmacological block of HCN channels with the antagonist ZD7288 applied via reverse microdialysis in the ventrobasal thalamus (VB) of freely moving male Genetic Absence Epilepsy Rats from Strasbourg decreases TC neuron firing and abolishes spontaneous ASs. A similar effect is observed on γ-hydroxybutyric acid-elicited ASs in normal male Wistar rats. Moreover, thalamic knockdown of HCN channels via virally delivered shRNA into the VB of male Stargazer mice, another genetic AS model, decreases spontaneous ASs and Ih-dependent electrophysiological properties of VB TC neurons. These findings provide the first evidence that block of TC neuron HCN channels prevents ASs and suggest that any potential anti-absence therapy that targets HCN channels should carefully consider the opposite role for cortical and thalamic Ih in the modulation of absence seizures.SIGNIFICANCE STATEMENT Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in the fine-tuning of cellular and network excitability and have been suggested to be a key element of the pathophysiological mechanism underlying absence seizures. However, the precise contribution of HCN channels in neocortical and thalamic neuronal populations to these nonconvulsive seizures is still controversial. In the present study, pharmacological block and genetic suppression of HCN channels in thalamocortical neurons in the ventrobasal thalamic nucleus leads to a marked reduction in absence seizures in one pharmacological and two genetic rodent models of absence seizures. These results provide the first evidence that block of TC neuron HCN channels prevents absence seizures.

KEYWORDS:

HCN channels; absence epilepsy; channelopathy; thalamocortical rhythms; thalamus

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center