PUBLICATION
Mutant zebrafish lacking slc25a22a show spontaneous seizures and respond to the anti-seizure medication valproic acid
- Authors
- Lee, S.H., Liang, T., Chandrasekaran, G., Zhang, J., Kim, S.S., Parvathi, S.V., Lee, S.W., Cho, E.S., Shin, H.Y., Yoon, Y.G., Jo, J., Bae, M.A., Choi, S.Y., Kim, M.K.
- ID
- ZDB-PUB-250621-4
- Date
- 2025
- Source
- Disease models & mechanisms 18: (Journal)
- Registered Authors
- Choi, Seok-Yong, Lee, So-Hyun
- Keywords
- slc25a22a, Anti-seizure medications, Epilepsy, Glutamate carrier, Mitochondria
- MeSH Terms
-
- Larva/drug effects
- Mitochondrial Membrane Transport Proteins*/deficiency
- Mitochondrial Membrane Transport Proteins*/genetics
- Mitochondrial Membrane Transport Proteins*/metabolism
- Animals
- Seizures*/drug therapy
- Seizures*/genetics
- Seizures*/physiopathology
- Epilepsy/drug therapy
- Epilepsy/genetics
- Epilepsy/physiopathology
- Anticonvulsants*/pharmacology
- Anticonvulsants*/therapeutic use
- Calcium/metabolism
- Zebrafish*/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Mutation*/genetics
- Humans
- Valproic Acid*/pharmacology
- Valproic Acid*/therapeutic use
- PubMed
- 40539845 Full text @ Dis. Model. Mech.
Citation
Lee, S.H., Liang, T., Chandrasekaran, G., Zhang, J., Kim, S.S., Parvathi, S.V., Lee, S.W., Cho, E.S., Shin, H.Y., Yoon, Y.G., Jo, J., Bae, M.A., Choi, S.Y., Kim, M.K. (2025) Mutant zebrafish lacking slc25a22a show spontaneous seizures and respond to the anti-seizure medication valproic acid. Disease models & mechanisms. 18:.
Abstract
Epilepsy is a neurological disorder associated with abnormal neuronal activity in the central nervous system, resulting in recurrent seizures. Various anti-seizure medications (ASMs) are effective against epilepsy. However, approximately one-third of patients still do not respond to currently available ASMs either alone or in combination because the etiology of their epilepsy remains unclear. To create a novel zebrafish epilepsy model, we analyzed the exomes of 400 Korean patients with epilepsy via whole-exome sequencing. We found 39 candidate genes and investigated these genes through in situ hybridization and loss-of-function studies, identifying SLC25A22, encoding a mitochondrial glutamate carrier, as a potential epilepsy gene. Subsequently, we generated zebrafish slc25a22a mutants and observed that they displayed spontaneous seizures, high-voltage deflections in local field potentials, and elevated Ca2+ levels propagating from the forebrain to the spinal cord. Of nine ASMs tested, valproic acid (VPA) was able to suppress spontaneous seizure activities in slc25a22a mutant larvae, highlighting the unique anti-seizure effect of VPA in this model. Our findings provide valuable insights into the pathogenesis of epilepsy and suggest slc25a22a as a potential target for novel ASM development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping