Triggering Migraine Aura: Dissecting the Neurobiological Basis 18
About one-third of people with migraine experience that the headache phase is preceded or accompanied by transient neurological disturbances, referred to as migraine aura. The physiological basis of the aura phase is thought be cortical spreading depolarization (CSD), a self-propagating wave of depolarization across the cerebral cortex that disrupts ionic gradients and is followed by cerebral hyperperfusion.
Recent scientific discoveries by our team have identified CGRP and levcromakalim, an opener of ATP-sensitive potassium (KATP) channels, as the first possible pharmacological inducers of migraine aura. This opens new avenues for research that might explain the enigmatic relationship between migraine aura and migraine pain. Our approach is to use FHM mice with the known migraine-specific mutations (in either the CACNA1A or ATP1A2 gene, expressed in neurons and glial cells, respectively), as well as intercrosses. These mice are ideal because specific genotypes experience spontaneous migraine-like attacks, mirroring the human condition.
We will conduct a series of experiments with administration of CGRP or levcromakalim both systematically (affecting the whole body) and locally (directly in the brain or onto the meninges). The expected results will provide critical insights into the initial phases of migraine attacks, particularly the site(s) and mechanism(s) of action leading to migraine aura. Electrophysiological recordings will capture the occurrence of CSD, while the behavioral pain response is assessed using headache-relevant grimace scoring.
Sub-projects exploring migraine aura
Sub-Project 5: Induction of Migraine Aura and Migraine Pain in FHM Mutant Mice in Response to CGRP and KATP Channel Opening
Objective:
To determine whether CGRP and levcromakalim, a KATP channel opener, increase the likelihood of CSD events in FHM mutant mice and, if so, identify the brain regions where these events originate. We will also examine the extent of CSD propagation through the cortex and other areas of the brain, as well as assess the corresponding behavioral pain responses in FHM mutant mice.
Potential Significance:
The use of a novel migraine-mutant mouse model with spontaneous CSD events allows us to dissect migraine aura initiation and termination like never before. The identification of localized alterations in brain activity might also provide critical insights into the neurobiological linkage between migraine aura and migraine pain.
Sub-Project 6: Modulation of Migraine Aura and Migraine Pain by CGRP and KATP Channel Opening in FHM Mutant Mice
Objective:
To examine whether CGRP and KATP channel opening can modulate CSD thresholds and migraine-like pain behaviors in FHM mutant mice.
Potential Significance:
Our findings offer novel insights into the modulation of migraine aura and pain via molecular mechanisms impacting CSD thresholds. These results will have immense impact due to the use of FHM mutant mice, which harbor the same gene mutations as found in people with hemiplegic migraine. Hence, FHM mutant mice are susceptible to CSD and more alike people with migraine with aura. The comparison of effects in wild-type and FHM mutant mice will also help discern if the observed effects are specific to the migraine-susceptible phenotype or are generalizable across genotypes.