Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat

K(ir)5.1 is an inwardly rectifying potassium (K(ir)) channel subunit abundantly expressed in the kidney and brain. We previously established the physiologic consequences of a Kcnj16 (gene encoding K(ir)5.1) knockout in the Dahl salt-sensitive rat (SS(Kcnj16–/–)), which caused electrolyte/pH dysregulation and high-salt diet–induced mortality. Since K(ir) channel gene mutations may alter neuronal excitability and are linked to human seizure disorders, we hypothesized that SS(Kcnj16–/–) rats would exhibit neurological phenotypes, including increased susceptibility to seizures. SS(Kcnj16–/–) 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 SS(Kcnj16–/–) 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 K(ir)5.1 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.