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.

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

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.

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 Early-onset familial hemiplegic migraine due to a novel SCN1A mutation

Cephalalgia ◽  
2016 ◽  
Vol 36 (13) ◽  
pp. 1238-1247 ◽  
Author(s):  
Chunxiang Fan ◽  
Stefan Wolking ◽  
Frank Lehmann-Horn ◽  
Ulrike BS Hedrich ◽  
Tobias Freilinger ◽  
...  
Keyword(s):  
Early Onset ◽  
Novel Mutation ◽  
Familial Hemiplegic Migraine ◽  
Inhibitory Neurons ◽  
Clinical Genetic ◽  
Hemiplegic Migraine ◽  
Gene Encoding ◽  
Whole Cell Patch Clamp ◽  
Steady State Inactivation ◽  
Epilepsy Gene

Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+ channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with β1 and β2 subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.

The familial hemiplegic migraine type 1 mutation K1336E affects direct G protein-mediated regulation of neuronal P/Q-type Ca2+ channels

Cephalalgia ◽  
2013 ◽  
Vol 33 (6) ◽  
pp. 398-407 ◽  
Author(s):  
Edgar Garza-López ◽  
Ricardo González-Ramírez ◽  
María A Gandini ◽  
Alejandro Sandoval ◽  
Ricardo Felix
Keyword(s):  
G Protein ◽  
Familial Hemiplegic Migraine ◽  
Inactivation Kinetics ◽  
Missense Mutations ◽  
Hemiplegic Migraine ◽  
Gene Encoding ◽  
Dominant Form ◽  
Hek 293 ◽  
Autosomal Dominant Form

Background Familial hemiplegic migraine type 1 (FHM-1) is an autosomal dominant form of migraine with aura characterized by recurrent migraine, hemiparesis and ataxia. FHM-1 has been linked to missense mutations in the CACNA1A gene encoding the pore-forming subunit of the neuronal voltage-gated P/Q-type Ca2+ channel (CaV2.1α1). Methods Here, we explored the effects of the FHM-1 K1336E mutation on G protein-dependent modulation of the recombinant P/Q-type channel. The mutation was introduced into the human CaV2.1α1 subunit and its functional consequences investigated after heterologous expression in HEK-293 cells using patch-clamp recordings. Results Functional analysis of the K1336E mutation revealed a reduction of Ca2+ current densities, a ∼10 mV left-shift in the current-voltage relationship, and the slowing of current inactivation kinetics. When co-expressed along with the human μ-opioid receptor, application of the agonist DAMGO inhibited whole-cell currents through both the wild-type and the mutant channels. Prepulse facilitation was also reduced by the K1336E mutation. Likewise, the kinetic analysis of the onset and decay of facilitation showed that the mutation affects the apparent dissociation and reassociation rates of the Gβγ dimer from the channel complex. Conclusions These results suggest that the extent of G-protein-mediated inhibition is significantly reduced in the K1336E mutant CaV2.1 Ca2+ channels. This alteration would contribute to render the neuronal network hyperexcitable, possibly as a consequence of reduced presynaptic inhibition, and may help to explain some aspects of the FHM-1 pathophysiology.

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