Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2.
Familial hemiplegic migraine type 2 (FHM2) is an autosomal dominant form of migraine with aura that is caused by mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain. We generated the first FHM2 knock-in mouse model carrying the hum...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-06-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002129&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849470245462343680 |
|---|---|
| author | Loredana Leo Lisa Gherardini Virginia Barone Maurizio De Fusco Daniela Pietrobon Tommaso Pizzorusso Giorgio Casari |
| author_facet | Loredana Leo Lisa Gherardini Virginia Barone Maurizio De Fusco Daniela Pietrobon Tommaso Pizzorusso Giorgio Casari |
| author_sort | Loredana Leo |
| collection | DOAJ |
| description | Familial hemiplegic migraine type 2 (FHM2) is an autosomal dominant form of migraine with aura that is caused by mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain. We generated the first FHM2 knock-in mouse model carrying the human W887R mutation in the Atp1a2 orthologous gene. Homozygous Atp1a2(R887/R887) mutants died just after birth, while heterozygous Atp1a2(+/R887) mice showed no apparent clinical phenotype. The mutant α2 Na,K-ATPase protein was barely detectable in the brain of homozygous mutants and strongly reduced in the brain of heterozygous mutants, likely as a consequence of endoplasmic reticulum retention and subsequent proteasomal degradation, as we demonstrate in transfected cells. In vivo analysis of cortical spreading depression (CSD), the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse. Since several lines of evidence involve a specific role of the glial α2 Na,K pump in active reuptake of glutamate from the synaptic cleft, we hypothesize that CSD facilitation in the FHM2 mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical excitatory neurotransmission. The demonstration that FHM2 and FHM1 mutations share the ability to facilitate induction and propagation of CSD in mouse models further support the role of CSD as a key migraine trigger. |
| format | Article |
| id | doaj-art-b4355d38ee0a4d7a82d6e398eefa9be8 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2011-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-b4355d38ee0a4d7a82d6e398eefa9be82025-08-20T03:25:12ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-06-0176e100212910.1371/journal.pgen.1002129Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2.Loredana LeoLisa GherardiniVirginia BaroneMaurizio De FuscoDaniela PietrobonTommaso PizzorussoGiorgio CasariFamilial hemiplegic migraine type 2 (FHM2) is an autosomal dominant form of migraine with aura that is caused by mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain. We generated the first FHM2 knock-in mouse model carrying the human W887R mutation in the Atp1a2 orthologous gene. Homozygous Atp1a2(R887/R887) mutants died just after birth, while heterozygous Atp1a2(+/R887) mice showed no apparent clinical phenotype. The mutant α2 Na,K-ATPase protein was barely detectable in the brain of homozygous mutants and strongly reduced in the brain of heterozygous mutants, likely as a consequence of endoplasmic reticulum retention and subsequent proteasomal degradation, as we demonstrate in transfected cells. In vivo analysis of cortical spreading depression (CSD), the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse. Since several lines of evidence involve a specific role of the glial α2 Na,K pump in active reuptake of glutamate from the synaptic cleft, we hypothesize that CSD facilitation in the FHM2 mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical excitatory neurotransmission. The demonstration that FHM2 and FHM1 mutations share the ability to facilitate induction and propagation of CSD in mouse models further support the role of CSD as a key migraine trigger.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002129&type=printable |
| spellingShingle | Loredana Leo Lisa Gherardini Virginia Barone Maurizio De Fusco Daniela Pietrobon Tommaso Pizzorusso Giorgio Casari Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genetics |
| title | Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. |
| title_full | Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. |
| title_fullStr | Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. |
| title_full_unstemmed | Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. |
| title_short | Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. |
| title_sort | increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2 |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002129&type=printable |
| work_keys_str_mv | AT loredanaleo increasedsusceptibilitytocorticalspreadingdepressioninthemousemodeloffamilialhemiplegicmigrainetype2 AT lisagherardini increasedsusceptibilitytocorticalspreadingdepressioninthemousemodeloffamilialhemiplegicmigrainetype2 AT virginiabarone increasedsusceptibilitytocorticalspreadingdepressioninthemousemodeloffamilialhemiplegicmigrainetype2 AT mauriziodefusco increasedsusceptibilitytocorticalspreadingdepressioninthemousemodeloffamilialhemiplegicmigrainetype2 AT danielapietrobon increasedsusceptibilitytocorticalspreadingdepressioninthemousemodeloffamilialhemiplegicmigrainetype2 AT tommasopizzorusso increasedsusceptibilitytocorticalspreadingdepressioninthemousemodeloffamilialhemiplegicmigrainetype2 AT giorgiocasari increasedsusceptibilitytocorticalspreadingdepressioninthemousemodeloffamilialhemiplegicmigrainetype2 |