Increased excitability and synaptic transmission of GABAergic neurons derived from a patient with alternating hemiplegia of childhood
5 affiliations
- 1Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080 Republic of Korea
- 2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- 3Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Seoul, 03080 Republic of Korea
- 4Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
- 5Medical Research Center, Neuroscience Research Institute, Seoul National University, Seoul, Republic of Korea
Abstract
Mutations in ATP1A3, which encodes the α3 subunit of the Na⁺/K⁺-ATPase, are associated with various neurological disorders, including alternating hemiplegia of childhood (AHC). Although several studies have used mouse models to investigate ATP1A3 function, their translational relevance remains limited due to species-specific differences in neurodevelopment and neural circuitry. Additionally, previous patient-derived induced pluripotent stem cell (iPSC) models were limited by their focus on excitatory neurons. Given the prominent expression of the α3 isoform in GABAergic neurons, we investigated GABAergic neuron cell type-specific dysfunction using AHC-patient-derived iPSC. This iPSC was generated from the urinary cells of a control subject and a patient with AHC harboring a heterozygous ATP1A3E815K/+ mutation and subsequently differentiated into GABAergic neurons. AHC-patient-derived GABAergic neurons exhibited significantly reduced ouabain-sensitive pump currents, indicating a loss-of-function effect of the mutation. Pump deficiency is accompanied by intrinsic hyperexcitability and increased spontaneous inhibitory synaptic transmission. These findings provide direct evidence of GABAergic neuronal dysfunction in AHC and highlight the importance of GABAergic pathology in ATP1A3-related disorders.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13041-026-01338-7.
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BibTeX
@article{kim2026increased,
title = {{Increased excitability and synaptic transmission of GABAergic neurons derived from a patient with alternating hemiplegia of childhood}},
author = {Min-Gyun Kim and Hien Bao Dieu Thai and Woojoong Kim and Sol Choi and Heeju Kim and Kyoung-Doo Hwang and Jangsup Moon and Yong-Seok Lee and Byung Chan Lim},
journal = {Molecular Brain},
year = {2026},
month = aug,
doi = {10.1186/s13041-026-01338-7},
url = {https://doi.org/10.1186/s13041-026-01338-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Increased excitability and synaptic transmission of GABAergic neurons derived from a patient with alternating hemiplegia of childhood
AU - Min-Gyun Kim
AU - Hien Bao Dieu Thai
AU - Woojoong Kim
AU - Sol Choi
AU - Heeju Kim
AU - Kyoung-Doo Hwang
AU - Jangsup Moon
AU - Yong-Seok Lee
AU - Byung Chan Lim
PY - 2026
DA - 2026/08/11
JO - Molecular Brain
DO - 10.1186/s13041-026-01338-7
UR - https://doi.org/10.1186/s13041-026-01338-7
AB - Mutations in ATP1A3, which encodes the α3 subunit of the Na⁺/K⁺-ATPase, are associated with various neurological disorders, including alternating hemiplegia of childhood (AHC). Although several studies have used mouse models to investigate ATP1A3 function, their translational relevance remains limited due to species-specific differences in neurodevelopment and neural circuitry. Additionally, previous patient-derived induced pluripotent stem cell (iPSC) models were limited by their focus on excitatory neurons. Given the prominent expression of the α3 isoform in GABAergic neurons, we investigated GABAergic neuron cell type-specific dysfunction using AHC-patient-derived iPSC. This iPSC was generated from the urinary cells of a control subject and a patient with AHC harboring a heterozygous ATP1A3E815K/+ mutation and subsequently differentiated into GABAergic neurons. AHC-patient-derived GABAergic neurons exhibited significantly reduced ouabain-sensitive pump currents, indicating a loss-of-function effect of the mutation. Pump deficiency is accompanied by intrinsic hyperexcitability and increased spontaneous inhibitory synaptic transmission. These findings provide direct evidence of GABAergic neuronal dysfunction in AHC and highlight the importance of GABAergic pathology in ATP1A3-related disorders. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13041-026-01338-7.
SN - 1756-6606
ER -