Migraines in Mice Explain Human Experience in Hereditary Migraine Subtype
Abstract & Commentary
By Dara Jamieson, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Jamieson reports she is a retained consultant for Boehringer Ingelheim, Merck, and Ortho-McNeil, and is on the speaker's bureau for Boehringer Ingelheim and Merck.
Synopsis: A knock-in mouse model of a specific variant of familial hemiplegic migraine links the clinical manifestations of this rare migraine symptom with the triggering and propagation of cortical spreading depression and other unique characteristics of migraine.
Source: van den Maagdenberg AM, et al. High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Ann Neurol 2010;67:85-98.
Familial hemiplegic migraine (fhm), an autosomal dominant subtype of migraine associated with attacks of transient hemiparesis and other neurological aura symptoms, has been studied to elucidate the pathogenetic mechanisms of more common migraine types. Overlapping features of FHM and migraine both with and without aura validate the use of this rare migraine subtype, which has been linked to three specific genes. FHM1 is caused by mutations in the CACNA1A gene that encodes the pore-forming subunit of neuronal Ca(V)2.1 Ca(2+) channels. In humans, the S218L CACNA1A mutation variant of FHM1 causes a dramatic hemiplegic migraine syndrome that is associated with slowly progressive cerebellar ataxia, seizures, and severe, sometimes fatal, brain edema, often triggered by mild head trauma.
Animal models have been invaluable in analyzing the phenotypic, molecular, and electrophysiological consequences of human disease, and are especially applicable to migraine. Researchers from Leiden University Medical Center studied the mechanisms for the S218L syndrome using transgenic knock-in mice bearing the S218L missense mutation in the mouse CACNA1A gene.
The CACNA1A (S218L) mice, who faithfully mimicked the associated clinical features of the human S218L syndrome, were phenotypically normal between attacks except for mild cerebellar ataxia. Their poor performance on ataxia testing correlated pathologically with reduced arborization of cerebellar Purkinje neurons. These mice also had decreased life expectancy with death due to lung edema, perhaps correlated with sudden seizure-associated death, and exhibited significant brain edema after mild head impact. S218L neurons exhibited a gene dosage-dependent negative shift in voltage dependence of Ca(V)2.1 channel activation, resulting in enhanced neurotransmitter release at the neuromuscular junction. CACNA1A (S218L) mice also display an exquisite sensitivity to cortical spreading depression (CSD), the pathophysiological correlate of the migraine aura, with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus. This response correlates clinically with the increased sensitivity of the FHM1 S218L brain to even mild stimuli such as low-impact head trauma. The particularly low CSD threshold and the tendency to respond with multiple CSD events after a single stimulus indicate that the S218L cortex is highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. In comparison, knock-in mice for another variant of FHM1, the R192Q CACNA1A mutation, which in humans causes a milder form of hemiplegic migraine, typically exhibited only a single CSD event after one triggering stimulus.
Migraine, in its multiple clinical manifestations, afflicts millions of Americans and, despite recent advances in its acute treatment and prevention, is associated with extraordinary disability. The S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema. However, the most disabling aspect of migraine for most sufferers is the severe head pain with accompanying nausea and vomiting. The mice migraineurs, who mimic a rare migraine variant, do not indicate if they experience head pain and nausea so while the mouse model is a promising first step toward understanding the pathophysiology of migraine and having a substrate on which to test new therapies, more investigation is needed before all the mysteries of migraine are revealed. An animal model is a crucial first step and the work of the researchers from the Leiden University Medical Center illustrates the important contribution of the judicious use of animal models to our understanding and treatment of human disease.