Dynamics of Interneurons in the Presence of a Sodium Channel Mutation

Abstract

Background: Familial Hemiplegic Migraine is a genetic migraine which is caused by specific mutations mostly affecting interneurons’ membrane ion transport. The mutations cause an increase in the persistent sodium current, which is thought to be the cause of neuronal hyperexcitability and, consequently, migraine. We investigate the electrophysiological effects of SCN1A mutations on the Nav1.1 ionic channel that are involved in Familial Hemiplegic Migraine of type 3 (FHM3). Moreover, we study the effect of a sodium channel blocker as a therapeutic solution.Methods: We modified a previously published interneuron dynamical model and studied the effect of an increased persistent sodium current. Moreover, we investigated the effect of a sodium channel blocker. The effects of persistent current and channel blocker were represented by 2 parameters in the model. Concerning the model, we classified the bifurcation that causes the onset of the tonic firing when the input current is increased. Moreover, we calculated the states of phase lock for 2 coupled neurons as a function of the input current to the neuron, for both electrical and chemical synapses; when feasible a reduction to second order of accuracy with isostable coordinate reduction was used. Additionally, we calculated the metabolic efficiency and consumption of the neuron while in the firing regime. Every analysis reported above was performed for different values of persistent sodium current and blocker concentration.Results: We observed that, opposing the current clinical hypothesis, the mutation causes a decrease in the firing frequency in the FHM3 neuron model. Moreover, the increase in persistent sodium current causes an increase in the metabolic cost of the firing regime and an increase in ionic currents overlap, which is a marker of inefficiency of the action potential. Moreover, the mutation causes an increase in synchrony for the synaptic coupling of 2 neurons. The channel blocker has an effect opposed to the one of the mutation in a dose dependent way and is able to partially restore the wild type properties of the neuron.Conclusions: Our results suggest that hyperexcitability may not be the only cause for the onset of migraine, but more than one mechanism, including metabolic stress, may be active in causing the migraine phenotype.