Increased excitability and synaptic transmission of GABAergic neurons derived from a patient with alternating hemiplegia of childhood

Abstract

Abstract

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 ATP1A3 E815K/+ 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.