Loss of HCN1 subunits causes absence epilepsy in rats.

Abstract

Hyperpolarized-activated cyclic nucleotide-gated (HCN) channels underlie hyperpolarization-activated current (Ih) and are involved in controlling the excitability and electrical responsiveness of neurons. Absence epilepsy is clinically defined by a sudden, brief impairment of consciousness and behavioral arrest. Spike-and-wave discharges (SWDs) on electroencephalograms (EEG) are a diagnostic hallmark of absence epilepsy. In rat models of absence epilepsy, impaired function or expression of HCN1, a subtype of HCN channels, has been found. Here, to evaluate whether HCN1 deficiency causes absence epilepsy in rats, we developed Hcn1-knockout rats by transcription activator-like effector nuclease mutagenesis. The cortical and hippocampal pyramidal neurons of these rats displayed a significant reduction of Ih, a pronounced hyperpolarizing shift of the resting membrane potential, and increased input resistance, which indicated that the Hcn1-knockout rats were deficient in HCN1 function. The Hcn1-knockout rats were also more vulnerable to pentylenetetrazol-induced acute convulsions. More importantly, they exhibited spontaneous SWDs, which were accompanied by behavioral arrest, both of which were suppressed by ethosuximide. These results confirm the involvement of the HCN1 subunit in the regulation of input resistance and provide direct evidence that a deficiency of HCN1 caused absence epilepsy in rats.

• Authors: Ai Nishitani, Naofumi Kunisawa, Taketoshi Sugimura, Kazuaki Sato, Yusaku Yoshida, Toshiro Suzuki, Tetsushi Sakuma, Takashi Yamamoto, Masahide Asano, Yasuhiko Saito, Yukihiro Ohno, Takashi Kuramoto
• Journal: Brain research (Brain Res) Vol. 1706 Pg. 209-217 (03 01 2019) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 30408474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Cyclic Nucleotide-Gated Cation Channels
• Hcn1 protein, rat
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
• Potassium Channels

Topics

• Action Potentials (physiology)
• Animals
• Cerebral Cortex (metabolism)
• Cyclic Nucleotide-Gated Cation Channels (metabolism)
• Disease Models, Animal
• Electroencephalography
• Epilepsy, Absence (etiology, metabolism)
• Gene Knockout Techniques
• Hippocampus (metabolism)
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (genetics, metabolism, physiology)
• Male
• Membrane Potentials (physiology)
• Neurons (metabolism)
• Patch-Clamp Techniques
• Potassium Channels (genetics, metabolism, physiology)
• Pyramidal Cells (physiology)
• Rats
• Rats, Inbred F344
• Seizures (metabolism)