PUBLICATION

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

Authors
Dogra, D., Meza-Santoscoy, P.L., Gavrilovici, C., Rehak, R., de la Hoz, C.L.R., Ibhazehiebo, K., Rho, J.M., Kurrasch, D.M.
ID
ZDB-PUB-230521-37
Date
2023
Source
Epilepsia   64(8): 2186-2199 (Journal)
Registered Authors
Ibhazehiebo, Kingsley, Kurrasch, Deborah, Rehak, Renata
Keywords
KCNA1, carbamazepine, epilepsy, episodic ataxia type 1, zebrafish
MeSH Terms
  • Animals
  • Ataxia/complications
  • Ataxia/drug therapy
  • Ataxia/genetics
  • Carbamazepine/pharmacology
  • Carbamazepine/therapeutic use
  • Epilepsy*
  • Humans
  • Kv1.1 Potassium Channel/genetics
  • Mice
  • Seizures/complications
  • Zebrafish*
PubMed
37209379 Full text @ Epilepsia
Abstract
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 only provide partial relief to 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.
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 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.
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.
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.
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Human Disease / Model
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