Abstract
The ATP1A2 coding α2 subunit of Na,K‐ATPase, which is predominantly located in astrocytes, is a causative gene of familial hemiplegic migraine type 2 (FHM2). FHM2 model mice (Atp1a2tmCKwk/+) are susceptible to cortical spreading depression (CSD), which is profoundly related to migraine aura and headache. However, astrocytic properties during CSD have not been examined in FHM2 model mice. Using Atp1a2tmCKwk/+ crossed with transgenic mice expressing G‐CaMP7 in cortical neurons and astrocytes (Atp1a2+/−), we analyzed the changes in Ca2+ concentrations during CSD. The propagation speed of Ca2+ waves and the percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/− were higher than those in wild‐type mice. Increased percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/− may contribute to FHM2 pathophysiology.
Highlights
Migraine is a common disorder characterized by recurrent debilitating headache attacks [1] that are preceded by aura in a third of patients [2]
A decreased threshold for Cortical spreading depression (CSD) induction has been observed in FHM1 and familial hemiplegic migraine type 2 (FHM2) model animals [16,17]
CSD was induced by KCl application to the cortex, and propagating waves of Ca2+ were monitored by G-CaMP7 fluorescence using GLT-1-GCaMP7 mice
Summary
Migraine is a common disorder characterized by recurrent debilitating headache attacks [1] that are preceded by aura in a third of patients [2]. Animal experiments have indicated that CSD activates meningeal nociceptors in the trigeminovascular system [7] These results indicate that CSD is closely associated with migraine aura and headache [4]. Loss-of-function mutations in ATP1A2 causing FHM2 lead to the reduced clearance of glutamate and K+ by astrocytes [13]. Loss-of-function mutations in SCN1A causing FHM3 lead to the reduced inhibitory activity of inhibitory interneurons, which results in increased excitatory neuronal activity [14]. A decreased threshold for CSD induction has been observed in FHM1 and FHM2 model animals [16,17]. Atp1a2tmCKwk/+ mice showed enhanced fear/anxiety behaviors [21] and obesity by hyperphagia [23] These observations are consistent with the characteristics of FHM2 patients showing anxiety [24,25] and obesity [26], indicating that the Atp1a2tmCKwk/+ mouse reproduces FHM2 symptoms and is a useful model animal for clarifying the pathophysiology of FHM2. The properties of astrocytes and their possible influence on neuronal activity during CSD have not been examined in FHM2 model mice
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