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
Citation
Dogra, D., Meza-Santoscoy, P.L., Gavrilovici, C., Rehak, R., de la Hoz, C.L.R., Ibhazehiebo, K., Rho, J.M., Kurrasch, D.M. (2023) kcna1a mutant zebrafish model episodic ataxia type 1 (EA1) with epilepsy and respond to first-line therapy carbamazepine. Epilepsia. 64(8):2186-2199.
Abstract
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 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.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping