Abnormal synaptic <scp>C</scp>a<sup>2+</sup> homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice
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- Katharina Eikermann‐Haerter
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Michal Arbel‐Ornath
- Alzheimer Disease Research Laboratory Department of Neurology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Nilufer Yalcin
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Esther S. Yu
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Kishore V. Kuchibhotla
- Alzheimer Disease Research Laboratory Department of Neurology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Izumi Yuzawa
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Eloise Hudry
- Alzheimer Disease Research Laboratory Department of Neurology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Carli R. Willard
- Alzheimer Disease Research Laboratory Department of Neurology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Mihail Climov
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Fatmagul Keles
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Arianna M. Belcher
- Alzheimer Disease Research Laboratory Department of Neurology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Buse Sengul
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Andrea Negro
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Isaac A. Rosen
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Andrea Arreguin
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Michel D. Ferrari
- Department of Neurology Leiden University Medical Center Leiden the Netherlands
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- Arn M. J. M. van den Maagdenberg
- Department of Neurology Leiden University Medical Center Leiden the Netherlands
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- Brian J. Bacskai
- Alzheimer Disease Research Laboratory Department of Neurology Massachusetts General Hospital Harvard Medical School Charlestown MA
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- Cenk Ayata
- Neurovascular Research Laboratory Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA
Description
<jats:sec><jats:title>Objective</jats:title><jats:p>Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain‐of‐function of voltage‐gated Ca<jats:sub>V</jats:sub>2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α<jats:sub>1A</jats:sub> subunit of Ca<jats:sub>V</jats:sub>2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We employed in vivo multiphoton microscopy of the genetically encoded Ca<jats:sup>2+</jats:sup>‐indicator yellow cameleon to investigate synaptic morphology and [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> in FHM1 mice. To study CSD‐induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the Ca<jats:sub>V</jats:sub>2.1 gating modifier <jats:italic>tert‐</jats:italic>butyl dihydroquinone on CSD in vivo.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>FHM1 mutations elevate neuronal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a Ca<jats:sub>V</jats:sub>2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium‐overloaded neurons was increased. Neuronal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> surge during CSD was faster and larger, and post‐CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca<jats:sup>2+</jats:sup> homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs. Ann Neurol 2015;78:193–210</jats:p></jats:sec>
Journal
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- Annals of Neurology
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Annals of Neurology 78 (2), 193-210, 2015-07-06
Wiley
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Details 詳細情報について
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- CRID
- 1363670320422322816
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- ISSN
- 15318249
- 03645134
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- Data Source
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- Crossref