title: Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2.
abstract: Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 2: FHM2) is caused by loss-of-function mutations in α2 Na(+),K(+) ATPase (α2 NKA), an isoform almost exclusively expressed in astrocytes in adult brain. Cortical spreading depression (CSD), the phenomenon that underlies migraine aura and activates migraine headache mechanisms, is facilitated in heterozygous FHM2-knockin mice with reduced expression of α2 NKA The mechanisms underlying an increased susceptibility to CSD in FHM2 are unknown. Here, we show reduced rates of glutamate and K(+) clearance by cortical astrocytes during neuronal activity and reduced density of GLT-1a glutamate transporters in cortical perisynaptic astrocytic processes in heterozygous FHM2-knockin mice, demonstrating key physiological roles of α2 NKA and supporting tight coupling with GLT-1a. Using ceftriaxone treatment of FHM2 mutants and partial inhibition of glutamate transporters in wild-type mice, we obtain evidence that defective glutamate clearance can account for most of the facilitation of CSD initiation in FHM2-knockin mice, pointing to excessive glutamatergic transmission as a key mechanism underlying the vulnerability to CSD ignition in migraine.
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Clizia
authors.initials: C
authors.lastname: Capuani
authors.affiliation: Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy Center for Neurobiology of Aging, INRCA IRCCS, Ancona, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Melone
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Angelita
authors.initials: A
authors.lastname: Tottene
authors.affiliation: Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy Center for Neurobiology of Aging, INRCA IRCCS, Ancona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bragina
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Crivellaro
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zürich, Switzerland.
authors.forename: Mirko
authors.identifier: 0000-0002-7709-4127
authors.initials: M
authors.lastname: Santello
authors.affiliation: Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
authors.affiliation: Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy Center for Neurobiology of Aging, INRCA IRCCS, Ancona, Italy Fondazione di Medicina Molecolare, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Fiorenzo
authors.initials: F
authors.lastname: Conti
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy CNR Institute of Neuroscience, Padova, Italy daniela.pietrobon@unipd.it.
authors.forename: Daniela
authors.identifier: 0000-0002-5148-8670
authors.initials: D
authors.lastname: Pietrobon
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002540:Cerebral Cortex / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D020325:Migraine with Aura / Q000473:pathology* / Q000503:physiopathology*; D011188:Potassium / Q000378:metabolism*
chemical_list: D018698:Glutamic Acid; D011188:Potassium
keywords: Na+,K+
  ATPase; ceftriaxone; glutamate transporter; migraine; spreading depression