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Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat
Anna D. Manis, … , Matthew R. Hodges, Alexander Staruschenko
Anna D. Manis, … , Matthew R. Hodges, Alexander Staruschenko
Published November 24, 2020
Citation Information: JCI Insight. 2021;6(1):e143251. https://doi.org/10.1172/jci.insight.143251.
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Research Article Neuroscience

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

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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.

Authors

Anna D. Manis, Oleg Palygin, Elena Isaeva, Vladislav Levchenko, Peter S. LaViolette, Tengis S. Pavlov, Matthew R. Hodges, Alexander Staruschenko

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Figure 6

SSKcnj16–/– rats experience mortalities during 10 days of repeated seizure exposure.

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SSKcnj16–/– rats experience mortalities during 10 days of repeated seizu...
(A) Kaplan-Meier survival analysis of SSWT and SSKcnj16–/– rats during once-daily exposure to the 10 kHz acoustic tone. Repeated seizure induction (once daily for 10 days) resulted in mortalities in 37.5% of male and 12.5% female SSKcnj16–/– rats (n = 24 and 8, respectively). SSWT rats (n = 12) subjected to the same 10× protocol did not exhibit any mortalities. The survival curves depicted are significantly different (P = 0.0339, Mantel-Cox log-rank test). (B) Average seizure severity score (scores averaged over the 10 days for each animal) in male and female SSKcnj16–/– rats during the 10× protocol compared between rats fed a normal K+ diet (NKD, 0.36% K+) and a high-K+ diet (HKD, 1.41% K+). Dietary K+ supplementation reduced average seizure severity in male and female SSKcnj16–/– rats but did not alter seizure incidence (*P < 0.001, 2-way ANOVA with Holm-Sidak method of multiple comparisons). Female SSKcnj16–/– rats were found to have lower average severity than male rats on both diets. (C) Kaplan-Meier survival curve showing that dietary K+ supplementation prevented mortalities from repeated seizure exposure in SSKcnj16–/– rats (n = 10 and 6 for male and female rats, P = 0.0145). (D) Serum K+ was measured 24 hours after completion of the 10-day stimulation protocol (labeled “0”) and compared with values measured in age- and diet-matched naive rats (labeled “10”). 10× repeated seizure exposure in SSKcnj16–/– rats on the NKD resulted in decreased serum K+ compared with naive that in SSKcnj16–/– rats (*P < 0.001, 2-way ANOVA with Holm-Sidak method of multiple comparisons) (n = 13 and 10; 9 and 11; and 4 and 7 for control and 10 exposures in SSWT on NKD [black], SSKcnj16–/– on NKD [red], and SSKcnj16–/– rats on HKD [blue], correspondingly).

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