Activity-dependent calcium, oxygen, and vascular responses in a mouse model of familial hemiplegic migraine type 1.

Abstract

OBJECTIVE:

Familial hemiplegic migraine type 1 (FHM1) is a subtype of migraine with aura caused by a gain-of-function mutation in the pore-forming α1 subunit of CaV 2.1 (P/Q-type) calcium channels. However, the mechanisms underlying how the disease is brought about and the prolonged aura remain incompletely understood.

METHODS:

In the anesthetized FHM1 mouse model in vivo, we used two-photon microscopy to measure calcium changes in neurons and astrocytes during somatosensory stimulations and cortical spreading depression (CSD), the putative mechanism of the migraine aura. We combined it with assessment of local field potentials by electrophysiological recordings, cerebral blood flow by laser Doppler flowmetry, and oxygen consumption with measurement of the oxygen tissue tension.

RESULTS:

During spreading depression, the evoked increase in cytosolic Ca(2+) was larger and faster in FHM1 mice than wild-type (WT) mice. It was accompanied by larger increases in oxygen consumption in FHM1 mice, leading to tissue anoxia, but moderate hypoxia, in WT mice. In comparison, before CSD, Ca(2+) and hemodynamic responses to somatosensory stimulations were smaller in FHM1 mice than WT mice and almost abolished after CSD. The CSD-induced Ca(2+) changes were mitigated by the CaV 2.1 gating modifier, tert-butyl dihydroquinone.

INTERPRETATION:

Our findings suggest that tissue anoxia might be a mechanism for prolonged aura in FHM1. Reduced Ca(2+) signals during normal network activity in FHM1 as compared to WT mice may explain impaired neurovascular responses in the mutant, and these alterations could contribute to brain frailty in FHM1 patients. Ann Neurol 2016;80:219-232.

• Authors: Lila Khennouf, Bodil Gesslein, Barbara Lykke Lind, Arn M J M van den Maagdenberg, Martin Lauritzen
• Journal: Annals of neurology (Ann Neurol) Vol. 80 Issue 2 Pg. 219-32 (08 2016) ISSN: 1531-8249 [Electronic] United States
• PMID: 27314908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 American Neurological Association.

Chemical References

• Calcium Channels, N-Type
• voltage-dependent calcium channel (P-Q type)
• Oxygen
• Calcium

Topics

• Animals
• Astrocytes (metabolism)
• Calcium (metabolism)
• Calcium Channels, N-Type (genetics)
• Cerebellar Ataxia (genetics, metabolism, physiopathology)
• Cerebrovascular Circulation (physiology)
• Cortical Spreading Depression (genetics)
• Disease Models, Animal
• Electric Stimulation
• Gene Knock-In Techniques
• Male
• Membrane Potentials (physiology)
• Mice
• Mice, Transgenic
• Migraine Disorders (genetics, metabolism, physiopathology)
• Neurons (metabolism)
• Oxygen (metabolism)