Kir5.1 is an inwardly rectifying potassium (Kir) channel subunit abundantly expressed in the kidney and brain. We previously established the physiologic consequences of a Kcnj16 (gene encoding Kir5.1) knockout in the Dahl salt-sensitive rat (SSKcnj16–/–), which caused electrolyte/pH dysregulation and high-salt diet–induced mortality. Since Kir channel gene mutations may alter neuronal excitability and are linked to human seizure disorders, we hypothesized that SSKcnj16–/– rats would exhibit neurological phenotypes, including increased susceptibility to seizures. SSKcnj16–/– rats exhibited increased light sensitivity (fMRI) and reproducible sound-induced tonic-clonic audiogenic seizures confirmed by electroencephalography. Repeated seizure induction altered behavior, exacerbated hypokalemia, and led to approximately 38% mortality in male SSKcnj16–/– rats. Dietary potassium supplementation did not prevent audiogenic seizures but mitigated hypokalemia and prevented mortality induced by repeated seizures. These results reveal a distinct, nonredundant role for Kir5.1 channels in the brain, introduce a rat model of audiogenic seizures, and suggest that yet-to-be identified mutations in Kcnj16 may cause or contribute to seizure disorders.
Anna D. Manis, Oleg Palygin, Elena Isaeva, Vladislav Levchenko, Peter S. LaViolette, Tengis S. Pavlov, Matthew R. Hodges, Alexander Staruschenko
Description of behavioral scoring of seizure severity adapted from the Racine scale