Lessons from Familial Hemiplegic Migraine and Cortical Spreading Depression

Background Patients with familial hemiplegic migraine type 2 (FHM2) have a mutated ATP1A2 gene (encoding Na+,K+-ATPase α2 subunit) and show prolonged migraine aura. Cortical spreading depression (CSD), which involves mass depolarization of neurons and astrocytes that propagates slowly through the gray matter, is profoundly related to aura. Methods In two types of Atp1a2-defective heterozygous mice, Atp1a2tm1Kwk (C-KO) and Atp1a2tm2Kwk (N-KO), the sensitivity and responsiveness to CSD were examined under urethane anesthesia. Results In both cases, heterozygotes exhibited a low threshold for induction of CSD, faster propagation rate, slower recovery from DC deflection, and profound suppression of the electroencephalogram, compared to wild-type mice. A high dose of KCl elicited repeated CSDs for a longer period, with a tendency for a greater frequency of CSD occurrence in heterozygotes. The difference of every endpoint was slightly greater in N-KO than C-KO. Change of regional cerebral blood flow in response to CSD showed no significant difference. Conclusion Heterozygotes of Atp1a2-defective mice simulating FHM2 demonstrated high susceptibility to CSD rather than cortical vasoreactivity, and these effects may differ depending upon the knockout strategy for the gene disruption. These results suggest that patients with FHM2 may exhibit high susceptibility to CSD, resulting in migraine.

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EHMTI-0262. Dysregulation of inflammatory pathways in a familial hemiplegic migraine 1 mouse model after the induction of cortical spreading depression

The Journal of Headache and Pain ◽

10.1186/1129-2377-15-s1-b5 ◽

2014 ◽

Vol 15 (S1) ◽

Author(s):

B de Vries ◽

EE Eising ◽

R Shyti ◽

LS Vijfhuizen ◽

LAM Broos ◽

...

Keyword(s):

Mouse Model ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Inflammatory Pathways

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Cortical spreading depression and familial hemiplegic migraine 2015

The Journal of Headache and Pain ◽

10.1186/1129-2377-16-s1-a20 ◽

2015 ◽

Vol 16 (S1) ◽

Cited By ~ 2

Author(s):

Daniela Pietrobon

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine

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Characteristics of cortical spreading depression and c-Fos expression in transgenic mice having a mutation associated with familial hemiplegic migraine 2

Cephalalgia ◽

10.1177/0333102420929028 ◽

2020 ◽

Vol 40 (11) ◽

pp. 1177-1190

Author(s):

Chunhua Tang ◽

Miyuki Unekawa ◽

Mamoru Shibata ◽

Yutaka Tomita ◽

Yoshikane Izawa ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mice ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Orthologous Gene ◽

Underlying Mechanism ◽

Familial Hemiplegic Migraine ◽

Wild Type ◽

Hemiplegic Migraine ◽

Fos Expression

Background Cortical spreading depression is thought to be the underlying mechanism of migraine aura. In 2006, three relatives having the point mutation E700K in ATP1A2 exon 15 were diagnosed with familial hemiplegic migraine 2 characterized by complicated forms of aura. Here, we generated a transgenic mouse model having the human E700K mutation in the Atp1a2 orthologous gene. Objective To investigate the characteristics of cortical spreading depression in a mouse model with E700K mutation in the Atp1a2. Methods Cortical spreading depression was induced by applying stepwise increases of KCl concentration or electrical stimulation intensity to C57BL/6J-Tg(Atp1a2*E700K)9151Kwk mice (Tg, both sexes) and corresponding wild-type animals. Under urethane anesthesia, the responsiveness and threshold to cortical spreading depression were examined and the distribution of c-Fos expression, a neuronal activity marker, was immunohistochemically determined. Results Overall, Tg mice showed significantly faster propagation velocity ( p < 0.01) and longer full-width-at-half-maximum ( p < 0.01) than wild-type animals, representing a slower recovery from direct current potential deflection. The cortical spreading depression threshold tended to be lower in Tg, especially in females. c-Fos-positive cells were significantly enhanced in the ipsilateral somatosensory cortex, piriform cortex, amygdala and striatum (each p < 0.05 vs. contralateral side). Numbers of c-Fos positive cells were significantly higher in the ipsilateral amygdala of Tg, as compared with wild-type animals ( p < 0.01). Conclusion The effect of cortical spreading depression may be greater in E700K transgenic mice than that in wild-type animals, while the threshold for cortical spreading depression shows little change. Higher c-Fos expression in the amygdala may indicate alterations of the limbic system in Tg, suggesting an enhanced linkage between cortical spreading depression and amygdala connectivity in familial hemiplegic migraine 2 patients.

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Increased Susceptibility to Cortical Spreading Depression in the Mouse Model of Familial Hemiplegic Migraine Type 2

PLoS Genetics ◽

10.1371/journal.pgen.1002129 ◽

2011 ◽

Vol 7 (6) ◽

pp. e1002129 ◽

Cited By ~ 129

Author(s):

Loredana Leo ◽

Lisa Gherardini ◽

Virginia Barone ◽

Maurizio De Fusco ◽

Daniela Pietrobon ◽

...

Keyword(s):

Mouse Model ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Increased Susceptibility

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Intracellular and Plasma Magnesium in Familial Hemiplegic Migraine and Migraine With and Without Aura

Cephalalgia ◽

10.1046/j.1468-2982.1994.1401029.x ◽

1994 ◽

Vol 14 (1) ◽

pp. 29-32 ◽

Cited By ~ 11

Author(s):

MC Smeets ◽

CB Vernooy ◽

JHM Souverijn ◽

MD Ferrari

Keyword(s):

Spreading Depression ◽

Autosomal Dominant ◽

Study Groups ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Dominant Type ◽

Intracellular Magnesium ◽

Migraine Pathophysiology ◽

Plasma Magnesium ◽

Autosomal Dominant Type

Familial hemiplegic migraine (FHM) is an autosomal dominant type of migraine and probably represents the most extreme end of migraine with aura. Reduced magnesium facilitates the development of spreading depression and possibly aura. Cellular magnesium levels are under genetic control. We hypothesized that FHM patients would have significantly reduced intracellular magnesium levels. We determined intracellular and plasma magnesium levels in blood of 38 afflicted and 11 non-afflicted members of three families with FHM and, in 32 migraine patients (9 with and 23 without aura) and 32 age and sex matched healthy controls. We found no significant differences between the magnesium levels in the five study groups. We conclude that reduced blood magnesium is unlikely to be related to migraine pathophysiology.

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Enhanced Subcortical Spreading Depression in Familial Hemiplegic Migraine Type 1 Mutant Mice

Journal of Neuroscience ◽

10.1523/jneurosci.5346-10.2011 ◽

2011 ◽

Vol 31 (15) ◽

pp. 5755-5763 ◽

Cited By ~ 79

Author(s):

K. Eikermann-Haerter ◽

I. Yuzawa ◽

T. Qin ◽

Y. Wang ◽

K. Baek ◽

...

Keyword(s):

Spreading Depression ◽

Familial Hemiplegic Migraine ◽

Mutant Mice ◽

Hemiplegic Migraine

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GABAergic neurons and NaV1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression

10.1101/2020.03.14.991158 ◽

2020 ◽

Author(s):

Oana Chever ◽

Sarah Zerimech ◽

Paolo Scalmani ◽

Louisiane Lemaire ◽

Alexandre Loucif ◽

...

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Familial Hemiplegic Migraine ◽

Gabaergic Neurons ◽

Glutamatergic Transmission ◽

Specific Mechanism ◽

Gain Of Function ◽

Glutamatergic Synaptic Transmission ◽

Type 3

AbstractCortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel neocortex-specific mechanism of CSD initiation and a novel pathological role of GABAergic neurons. Mutations of the NaV1.1 sodium channel (the SCN1A gene), which is particularly important for GABAergic neurons’ excitability, cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura. They induce gain-of-function of NaV1.1 and hyperexcitability of GABAergic interneurons in culture. However, the mechanism linking these dysfunctions to CSD and FHM3 has not been elucidated. Here, we show that NaV1.1 gain-of-function, induced by the specific activator Hm1a, or mimicked by optogenetic-induced hyperactivity of cortical GABAergic neurons, is sufficient to ignite CSD by spiking-generated extracellular K+ build-up. This mechanism is neocortex specific because, with these approaches, CSD was not generated in other brain areas. GABAergic and glutamatergic synaptic transmission is not required for optogenetic CSD initiation, but glutamatergic transmission is implicated in CSD propagation. Thus, our results reveal the key role of hyper-activation of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which is relevant for FHM3 and possibly also for other types of migraine.

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