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.
Highlights
Absence seizures (ASs), which consist of relatively brief periods of lack of consciousness accompanied by spike-and-wave discharges (SWDs) in the EEG, are a feature of many genetic generalized epilepsies and believed to be generated by abnormal neuronal activity in reciprocally connected neocortical and thalamic territories (Crunelli and Leresche, 2002; Blumenfeld, 2005)
Among the different voltage-dependent channels that may be involved in the pathophysiological mechanisms of these nonconvulsive seizures, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are present in the vast majority of cortical and thalamic neurons, have been extensively investigated (Huang et al, 2009; Noam et al, 2011; Reid et al, 2012)
We report that bilateral reverse microdialysis application of the HCN blocker ZD7288 into the ventrobasal thalamus (VB) blocks ASs in two well established absence models, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS; Depaulis et al, 2015) and the ␥-hydroxybutyric acid (GHB)-injected Wistar rats (Venzi et al, 2015), and decreases tonic, but not burst, firing in TC neurons of freely moving GAERS
Summary
Absence seizures (ASs), which consist of relatively brief periods of lack of consciousness accompanied by spike-and-wave discharges (SWDs) in the EEG, are a feature of many genetic generalized epilepsies and believed to be generated by abnormal neuronal activity in reciprocally connected neocortical and thalamic territories (Crunelli and Leresche, 2002; Blumenfeld, 2005). Among the different voltage-dependent channels that may be involved in the pathophysiological mechanisms of these nonconvulsive seizures, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are present in the vast majority of cortical and thalamic neurons, have been extensively investigated (Huang et al, 2009; Noam et al, 2011; Reid et al, 2012). It is difficult to draw any firm conclusion from these human studies since ASs are not the only phenotype present in these diverse forms of epilepsy. As far as cellular effects are concerned, in vitro studies have shown that blocking the Ih current that HCN channels generate in thalamocortical (TC) neurons enhances bicuculline-elicited synchronized thalamic activity resembling absence paroxysms by increasing burst firing in TC neurons (Bal and McCormick, 1996). This, together with the complexity of the diverse cellular and synaptic effects
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