Linking a genetic defect in migraine to spreading depression in a computational model.

Markus A Dahlem,Niklas Hübel,Julia Schumacher

doi:10.7717/peerj.379

Abstract

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. A mutation causing FHM type 3 (FHM3) has been identified in SCN1A encoding the Nav1.1 Na+ channel. This genetic defect affects the inactivation gate. While the Na+ tail currents following voltage steps are consistent with both hyperexcitability and hypoexcitability, in this computational study, we investigate functional consequences beyond these isolated events. Our extended Hodgkin–Huxley framework establishes a connection between genotype and cellular phenotype, i.e., the pathophysiological dynamics that spans over multiple time scales and is relevant to migraine with aura. In particular, we investigate the dynamical repertoire from normal spiking (milliseconds) to spreading depression and anoxic depolarization (tens of seconds) and show that FHM3 mutations render gray matter tissue more vulnerable to spreading depression despite opposing effects associated with action potential generation. We conclude that the classification in terms of hypoexcitability vs. hyperexcitability is too simple a scheme. Our mathematical analysis provides further basic insight into also previously discussed criticisms against this scheme based on psychophysical and clinical data.

Highlights

Familial hemiplegic migraine (FHM) is a rare monogenic, autosomal dominantly inherited syndrome with hemiparesis during the aura phase of migraine
We end with the Discussion where we focus on three topics: (i) the appropriateness of the terms hypoexcitable vs. hyperexcitable, (ii) the seemingly paradoxically increased susceptibility to spreading depression (SD) in the mutant model if one considers the firing rate, a measure that is usually used to quantify slow neural dynamics, and (iii) the inadequate concept of a threshold as a quantity measured by a single value
Our main result is that the mutant model is more susceptible to spreading depression (SD)

Summary

Introduction

Familial hemiplegic migraine (FHM) is a rare monogenic, autosomal dominantly inherited syndrome with hemiparesis during the aura phase of migraine. It has been proposed that all three phenotypes reflect hyperexcitability in the form of increased susceptibility for spreading depression (SD) (van den Maagdenberg et al, 2007; Pietrobon, 2010). To determine the electrophysiological consequences of such a genetic defect, we integrate a mutation of FHM3 into three types of computational models of neuronal. How to cite this article Dahlem et al (2014), Linking a genetic defect in migraine to spreading depression in a computational model. This allows us to bridge the gap between genotype and phenotype. We use a standard Hodgkin–Huxley model for action potentials (AP) (Hodgkin & Huxley, 1952) and a model of SD (Hubel, Scholl & Dahlem, 2014) to evaluate the change in the threshold of generating SD by tolerating various brief intervals of transient ischemic attacks. We use a model for anoxic depolarization (AD) (Zandt et al, 2011) that is derived from a seizure model (Cressman et al, 2009; Cressman et al, 2011) as a test of the robustness of our results

Methods

Results

Conclusion