Persistent sodium current blockers can suppress seizures caused by loss of low-threshold D-type potassium currents: Predictions from an in silico study of Kv1 channel disorders

Abstract

Objective: Ion channels belonging to subfamily A of voltage-gated potassium channels (Kv1) are highly expressed on axons, where they play a key role in determining resting membrane potential, in shaping action potentials, and in modulating action potential frequency during repetitive neuronal firing. We aimed to study the genesis of seizures caused by mutations affecting Kv1 channels and searched for potential therapeutic targets. Methods: We used a novel in silico model, the laminar cortex model (LCM), to examine changes in neuronal excitability and network dynamics associated with loss-of-function mutations in Kv1 channels. The LCM simulates the activities of a network of tens of thousands of interconnected neurons and incorporates the kinetics of 11 types of ion channel and three classes of neurotransmitter receptor. Changes in two types of potassium currents conducted by Kv1 channels were examined: slowly inactivating D-type currents and rapidly inactivating A-type currents. Effects on neuronal firing rate, action potential shape, and neuronal oscillation state were evaluated. A systematic parameter scan was performed to identify parameter changes that can reverse the effects of the changes. Results: Reduced axonal D-type currents led to lower firing threshold and widened action potentials, both lowering the seizure threshold. Two potential therapeutic targets for treating seizures caused by loss-of-function changes in Kv1 channels were identified: persistent sodium channels and NMDA receptors. Blocking persistent sodium channels restored the firing threshold and reduced action potential width. NMDA receptor antagonists reduced excitatory postsynaptic currents from excessive glutamate release related to widened action potentials. Significance: Riluzole reduces persistent sodium currents and excitatory postsynaptic currents from NMDA receptor activation. Our results suggest that this FDA-approved drug can be repurposed to treat epilepsies caused by mutations affecting axonal Kv1 channels.