Increased Susceptibility to Cortical Spreading Depression in the Mouse Model of Familial Hemiplegic Migraine Type 2

• DOI: 10.1371/journal.pgen.1002129
• Publication Date: 2011-06-23T16:59:04Z
• Authors: Loredana Leo; Lisa Gherardini; Virginia Barone; Maurizio De Fusco; Daniela Pietrobon; Tommaso Pizzorusso; Giorgio Casari
• Keywords: Familial hemiplegic migraine; Cortical Spreading Depression

Familial hemiplegic migraine type 2 (FHM2) is an autosomal dominant form of with aura that caused by mutations the α2-subunit Na,K-ATPase, isoform almost exclusively expressed in astrocytes adult brain. We generated first FHM2 knock-in mouse model carrying human W887R mutation 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 brain homozygous and strongly reduced mutants, likely as a consequence endoplasmic reticulum retention subsequent proteasomal degradation, we demonstrate transfected cells. In vivo analysis cortical spreading depression (CSD), phenomenon underlying aura, revealed decreased induction threshold increased velocity propagation mouse. Since several lines evidence involve specific role glial Na,K pump active reuptake glutamate from synaptic cleft, hypothesize CSD facilitation sustained inefficient clearance consequent excitatory neurotransmission. demonstration FHM1 share ability to facilitate models further support key trigger.