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

PeerJ. 2014 May 8:2:e379. doi: 10.7717/peerj.379. eCollection 2014.


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.

Keywords: Action potential; Anoxia; Familial hemiplegic migraine; Hodgkin–Huxley model; Hyperexcitability; Hypoexcitability; Inactivation; Ions; Potassium channel; Threshold.

Grants and funding

This work was supported by the Bundesministerium für Bildung und Forschung (BMBF 01GQ1001B, 01GQ1109) within the Bernstein Center of Computational Neuroscience Berlin. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.