Abnormal synaptic Ca2+ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice. Issue 2 (6th July 2015)

• Record Type: Journal Article
• Authors: Eikermann‐Haerter, Katharina; Arbel‐Ornath, Michal; Yalcin, Nilufer; Yu, Esther S.; Kuchibhotla, Kishore V.; Yuzawa, Izumi; Hudry, Eloise; Willard, Carli R.; Climov, Mihail; Keles, Fatmagul; Belcher, Arianna M.; Sengul, Buse; Negro, Andrea; Rosen, Isaac A.; Arreguin, Andrea; Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.; Bacskai, Brian J.; Ayata, Cenk
• Is Part Of: Annals of neurology. Volume 78:Issue 2(2015:Aug.)
• Page Start: 193
• Page End: 210
• Publication Date: 2015-07-06
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24449
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24449-sec-0001" sec-type="section"> <title>Objective</title> <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<sub>V</sub>2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α<sub>1A</sub> subunit of Ca<sub>V</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.</p> </sec> <sec id="ana24449-sec-0002" sec-type="section"> <title>Methods</title> <p>We employed in vivo multiphoton microscopy of the genetically encoded Ca<sup>2+</sup>‐indicator yellow cameleon to investigate synaptic morphology and [Ca<sup>2+</sup>]<sub>i</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<sub>V</sub>2.1 gating modifier <italic>tert‐</italic>butyl dihydroquinone on CSD in vivo.</p> </sec> <sec id="ana24449-sec-0003" sec-type="section"> <title>Results</title> <p>FHM1 mutations elevate neuronal [Ca<sup>2+</sup>]<sub>i</sub> and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a Ca<sub>V</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<sup>2+</sup>]<sub>i</sub> was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium‐overloaded neurons was increased. Neuronal [Ca<sup>2+</sup>]<sub>i</sub> surge during CSD was faster and larger, and post‐CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains.</p> </sec> <sec id="ana24449-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca<sup>2+</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</p> </sec> </abstract>