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

• DOI: 10.1523/jneurosci.0896-17.2018
• Publication Date: 2018-06-20T15:25:52Z
• Authors: François David; Nihan Çarçak; Szabina Furdan; Filiz Onat; Timothy Gould; Ádám Mészáros; Giuseppe Di Giovanni; Vivian M. Hernández; C. Savio Chan; Magor L. Lőrincz; Vincenzo Crunelli
• Keywords: HCN channel; Hyperpolarization; Bursting

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