Widespread c-Fos expression after cortical spreading depression; possible differences between two types of animal models of familial hemiplegic migraine 2

2017 ◽  
Vol 381 ◽  
pp. 947
Author(s):  
M. Unekawa ◽  
K. Ikeda ◽  
Y. Tomita ◽  
K. Kawakami ◽  
N. Suzuki
Keyword(s):  
Animal Models ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Familial Hemiplegic Migraine ◽  
Hemiplegic Migraine ◽  
Fos Expression

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

Cephalalgia ◽  
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.

Stress hormone corticosterone enhances susceptibility to cortical spreading depression in familial hemiplegic migraine type 1 mutant mice

2015 ◽  
Vol 263 ◽  
pp. 214-220 ◽  
Author(s):  
Reinald Shyti ◽  
Katharina Eikermann-Haerter ◽  
Sandra H. van Heiningen ◽  
Onno C. Meijer ◽  
Cenk Ayata ◽  
...  
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Familial Hemiplegic Migraine ◽  
Mutant Mice ◽  
Stress Hormone ◽  
Hemiplegic Migraine

Enhanced susceptibility to cortical spreading depression in two types of Na+,K+-ATPase α2 subunit-deficient mice as a model of familial hemiplegic migraine 2

Cephalalgia ◽  
2017 ◽  
Vol 38 (9) ◽  
pp. 1515-1524 ◽  
Author(s):  
Miyuki Unekawa ◽  
Keiko Ikeda ◽  
Yutaka Tomita ◽  
Kiyoshi Kawakami ◽  
Norihiro Suzuki
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Propagation Rate ◽  
Familial Hemiplegic Migraine ◽  
High Dose ◽  
High Susceptibility ◽  
Hemiplegic Migraine ◽  
Gene Encoding ◽  
Significant Difference ◽  
The Difference

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.

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

PLoS Genetics ◽  
2011 ◽  
Vol 7 (6) ◽  
pp. e1002129 ◽  
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

scholarly journals Cortical Spreading Depression—New Insights and Persistent Questions

Cephalalgia ◽  
2009 ◽  
Vol 29 (10) ◽  
pp. 1115-1124 ◽  
Author(s):  
A Charles ◽  
KC Brennan
Keyword(s):  
Brain Injury ◽  
Animal Models ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Exact Role ◽  
Definitive Evidence ◽  
Meaningful Information ◽  
Human Disorders ◽  
Functional Consequences

Since its original extensive description by Leao in 1944, thousands of publications have characterized the phenomenon of cortical spreading depression (CSD). Despite the attention that CSD has received over more than six decades, however, many fundamental questions regarding its initiation, propagation, functional consequences, and relationship to migraine and other human disorders remain unanswered. Advances in genetics and cellular imaging have led to important insights into the basic mechanisms of CSD, with increasing attention focused on specific neuronal ion channels, neurotransmitters and neuromodulators. In addition, there is growing recognition that astrocytes and the vasculature may play an active, rather than simply a passive or reactive role in CSD. Several recent descriptions of CSD in humans in the setting of brain injury provide definitive evidence that this phenomenon can occur and have important functional consequences in the human brain. Although the exact role of CSD in migraine has yet to be conclusively established, there is strong evidence that the investigation of CSD in animal models can provide meaningful information about migraine that can be translated into the clinical setting. This review will briefly address the extensive work that has been done on CSD over more than half a century, but focus primarily on more recent studies with a particular emphasis on relevance to migraine.

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

Cephalalgia ◽  
1994 ◽  
Vol 14 (1) ◽  
pp. 29-32 ◽  
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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