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.
| Original language | English |
|---|---|
| Pages (from-to) | 967-986 |
| Number of pages | 20 |
| Journal | EMBO Molecular Medicine |
| Volume | 8 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2016 |
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Keywords
- ceftriaxone
- glutamate transporter
- migraine
- Na,K ATPase
- spreading depression
ASJC Scopus subject areas
- Molecular Medicine
Cite this
Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2. / Capuani, Clizia; Melone, Marcello; Tottene, Angelita; Bragina, Luca; Crivellaro, Giovanna; Santello, Mirko; Casari, Giorgio; Conti, Fiorenzo; Pietrobon, Daniela.
In: EMBO Molecular Medicine, Vol. 8, No. 8, 01.08.2016, p. 967-986.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2
AU - Capuani, Clizia
AU - Melone, Marcello
AU - Tottene, Angelita
AU - Bragina, Luca
AU - Crivellaro, Giovanna
AU - Santello, Mirko
AU - Casari, Giorgio
AU - Conti, Fiorenzo
AU - Pietrobon, Daniela
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - ceftriaxone
KW - glutamate transporter
KW - migraine
KW - Na,K ATPase
KW - spreading depression
UR - http://www.scopus.com/inward/record.url?scp=84980018862&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84980018862&partnerID=8YFLogxK
U2 - 10.15252/emmm.201505944
DO - 10.15252/emmm.201505944
M3 - Article
C2 - 27354390
AN - SCOPUS:84980018862
VL - 8
SP - 967
EP - 986
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 8
ER -