Abstract
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.
Highlights
Epilepsy is among the most common neurological disorders and is characterized by a sustained increased susceptibility to hyperexcitable or hypersynchronized electrical activity in the brain, which can produce recurrent seizures [1, 2]
Given the association with EAST/SeSAME syndrome, we began to investigate this phenotype and hypothesized that the SSKcnj16–/– strain could be used as a monogenic model of audiogenic seizures, and we determined the parameters of acoustic stimuli to induce a robust, reproducible response
We found that SSKcnj16–/– rats consistently and reproducibly exhibited audiogenic seizures when presented with a 10 kHz acoustic stimulus for a 2-minute duration
Summary
Epilepsy is among the most common neurological disorders and is characterized by a sustained increased susceptibility to hyperexcitable or hypersynchronized electrical activity in the brain, which can produce recurrent seizures [1, 2]. Epilepsy represents a wide array of seizure disorders with substantial phenotypic and genetic heterogeneity, which can obscure understanding of the mechanisms behind refractory epilepsy and create a barrier to the development of effective therapeutic strategies. Seizure disorders are commonly associated with impairments in electrolyte homeostasis, and mutations in genes encoding ion channels are some of the few molecular causes that have been identified [7]. Animal models are necessary to elucidate the physiological consequences of mutations in specific ion channel genes, determine the effect of these mutations on neurological function and potential contribution to epileptogenesis, and to identify and evaluate novel therapeutic targets for the treatment of epilepsy
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