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Suppression of HCN channel function in thalamocortical neurons prevents genetically determined and pharmacologically induced absence seizures

66 Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the I h current they 67 generate contribute to the pathophysiological mechanisms of absence seizures (ASs), but their 68 precise role in neocortical and thalamic neuronal populations, the main components of the 69 network underlying AS generation remains controversial. In diverse genetic AS models, I h 70 amplitude is smaller in neocortical neurons and either larger or unchanged in thalamocortical 71 (TC) neurons compared to non-epileptic strains. A lower expression of neocortical HCN subtype 72 1 channels is present in genetic AS-prone rats and HCN2 Knock-Out mice exhibit ASs. 73 Furthermore, whereas many studies have characterized I h contribution to “absence -like ” 74 paroxysmal activity in vitro , no data is available on the specific role of cortical and thalamic 75 HCN channels in behavioural seizures. Here, we show that the pharmacological block of HCN 76 channels with the antagonist ZD7288 applied via reverse microdialysis in the ventrobasal 77 thalamus (VB) of freely moving male Genetic Absence Epilepsy Rats from Strasbourg decreases 78 TC neuron firing and abolishes spontaneous ASs. A similar effect is observed on γ - 79 hydroxybutyric acid-elicited ASs in normal male Wistar rats. Moreover, thalamic knockdown of 80 HCN channels via virally-delivered shRNA into the VB of male Stargazer mice, another genetic 81 AS model, decreases spontaneous ASs and I h -dependent electrophysiological properties of VB 82 TC neurons. These findings provide the first evidence that block of TC neuron HCN channels 83 prevents ASs and suggest that any potential anti-absence therapy that targets HCN channels 84 should carefully consider the opposite role for cortical and thalamic I h in the modulation of 85 absence seizures. 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 non- convulsive 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 of 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 ASs.