title: Abnormal synaptic Ca(2+) homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice.
abstract: OBJECTIVE
  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 CaV 2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV 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.
  
  
  METHODS
  We employed in vivo multiphoton microscopy of the genetically encoded Ca(2+)-indicator yellow cameleon to investigate synaptic morphology and [Ca(2+)]i 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 CaV 2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo.
  
  
  RESULTS
  FHM1 mutations elevate neuronal [Ca(2+)]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV 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(2+)]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca(2+)]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains.
  
  
  CONCLUSIONS
  Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca(2+) homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs.
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.affiliation: Alzheimer Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Michal
authors.initials: M
authors.lastname: Arbel-Ornath
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Yalcin
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Esther S
authors.initials: ES
authors.lastname: Yu
authors.affiliation: Alzheimer Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Kishore V
authors.initials: KV
authors.lastname: Kuchibhotla
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Yuzawa
authors.affiliation: Alzheimer Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Eloise
authors.initials: E
authors.lastname: Hudry
authors.affiliation: Alzheimer Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Carli R
authors.initials: CR
authors.lastname: Willard
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Mihail
authors.initials: M
authors.lastname: Climov
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Fatmagul
authors.initials: F
authors.lastname: Keles
authors.affiliation: Alzheimer Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Arianna M
authors.initials: AM
authors.lastname: Belcher
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Buse
authors.initials: B
authors.lastname: Sengul
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Negro
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Isaac A
authors.initials: IA
authors.lastname: Rosen
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arreguin
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Alzheimer Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.|Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000235:genetics; D006873:Hydroquinones / Q000494:pharmacology; D051379:Mice; D036641:Microscopy, Fluorescence, Multiphoton; D020325:Migraine with Aura / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D002118:Calcium; D020864:Calcium Channels, N-Type; D000252:Calcium-Transporting ATPases; D004791:Enzyme Inhibitors; D006873:Hydroquinones; C018855:2-tert-butylhydroquinone