Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat
Manis AD, Palygin O, Isaeva E, Levchenko V, LaViolette PS, Pavlov TS, Hodges MR, and Staruschenko A. Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat. JCI Insight 2020.
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 SS 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, non-redundant role for Kir5.1 channels in the brain, introduce a novel rat model of audiogenic seizures, and suggest yet to be identified mutations in Kcnj16 may cause or contribute to seizure disorders.
ePub ahead of print