kcna1a mutant zebrafish model episodic ataxia type 1 (EA1) with epilepsy and show response to first-line therapy carbamazepine.

Autor: Dogra D; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada., Meza-Santoscoy PL; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada., Gavrilovici C; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.; Departments of Pediatrics, Clinical Neurosciences, Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.; Departments of Neurosciences, Pediatrics, and Pharmacology, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California, USA., Rehak R; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada., de la Hoz CLR; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada., Ibhazehiebo K; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada., Rho JM; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.; Departments of Pediatrics, Clinical Neurosciences, Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.; Departments of Neurosciences, Pediatrics, and Pharmacology, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California, USA., Kurrasch DM; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Jazyk: angličtina
Zdroj: Epilepsia [Epilepsia] 2023 Aug; Vol. 64 (8), pp. 2186-2199. Date of Electronic Publication: 2023 Jun 04.
DOI: 10.1111/epi.17659
Abstrakt: Objective: KCNA1 mutations are associated with a rare neurological movement disorder known as episodic ataxia type 1 (EA1), and epilepsy is a common comorbidity. Current medications provide only partial relief for ataxia and/or seizures, making new drugs needed. Here, we characterized zebrafish kcna1a -/- as a model of EA1 with epilepsy and compared the efficacy of the first-line therapy carbamazepine in kcna1a -/- zebrafish to Kcna1 -/- rodents.
Methods: CRISPR/Cas9 mutagenesis was used to introduce a mutation in the sixth transmembrane segment of the zebrafish Kcna1 protein. Behavioral and electrophysiological assays were performed on kcna1a -/- larvae to assess ataxia- and epilepsy-related phenotypes. Real-time quantitative polymerase chain reaction (qPCR) was conducted to measure mRNA levels of brain hyperexcitability markers in kcna1a -/- larvae, followed by bioenergetics profiling to evaluate metabolic function. Drug efficacies were tested using behavioral and electrophysiological assessments, as well as seizure frequency in kcna1a -/- zebrafish and Kcna1 -/- mice, respectively.
Results: Zebrafish kcna1a -/- larvae showed uncoordinated movements and locomotor deficits, along with scoliosis and increased mortality. The mutants also exhibited impaired startle responses when exposed to light-dark flashes and acoustic stimulation as well as hyperexcitability as measured by extracellular field recordings and upregulated fosab transcripts. Neural vglut2a and gad1b transcript levels were disrupted in kcna1a -/- larvae, indicative of a neuronal excitatory/inhibitory imbalance, as well as a significant reduction in cellular respiration in kcna1a -/- , consistent with dysregulation of neurometabolism. Notably, carbamazepine suppressed the impaired startle response and brain hyperexcitability in kcna1a -/- zebrafish but had no effect on the seizure frequency in Kcna1 -/- mice, suggesting that this EA1 zebrafish model might better translate to humans than rodents.
Significance: We conclude that zebrafish kcna1a -/- show ataxia and epilepsy-related phenotypes and are responsive to carbamazepine treatment, consistent with EA1 patients. These findings suggest that kcna1 -/- zebrafish are a useful model for drug screening as well as studying the underlying disease biology.
(© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Databáze: MEDLINE
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