ATP1A3 E815K Disrupts Sodium Homeostasis and Excitability in Human Alternating Hemiplegia of Childhood Neurons

Alternating hemiplegia of childhood (AHC) is a rare, neurodevelopmental disorder often caused by de novo mutations in the ATP1A3 gene, which produces a specific protein involved in regulating sodium and potassium levels within neurons. The E815K variant of ATP1A3 is particularly prevalent in severe AHC cases, often leading to frequent seizures, muscle stiffness, and significant intellectual disability.

While this mutation has been shown to impair the pump's function in external systems and animal models, its impact on human neurons is less clear. To delve deeper, researchers converted skin cells from an AHC patient with the E815K mutation into neurons via a process known as induced pluripotent stem cell (iPSC) technology. These patient-derived neurons appeared to develop normally and connect as they should, maintaining typical communication patterns.

However, there was a significant difference in their sodium-potassium pump activity. Unlike other neurons, which showed robust pump function, the patient-derived neurons exhibited almost no pump activity. The sodium-potassium pump, crucial for maintaining the neuron's resting membrane potential and overall excitability, was largely absent in these cells.

As a result, these neurons displayed a depolarized resting potential, reduced resistance to electrical current input, and lower excitability. This led to fewer action potentials being generated in response to electrical stimulation and altered firing patterns. Notably, the density of voltage-gated sodium channels, which play a key role in neuronal excitability, was notably reduced in the patient neurons.

In summary, these findings demonstrate that the ATP1A3 E815K mutation disrupts the neuron's ability to regulate sodium levels, thereby altering the excitability of human neurons. This provides valuable insights into the molecular basis of AHC and offers a platform for studying potential treatments through drug testing on these patient-specific neurons.