| First Author | Aizawa H | Year | 2020 |
| Journal | Glia | Volume | 68 |
| Issue | 12 | Pages | 2631-2642 |
| PubMed ID | 32585762 | Mgi Jnum | J:297578 |
| Mgi Id | MGI:6474061 | Doi | 10.1002/glia.23874 |
| Citation | Aizawa H, et al. (2020) Glial glutamate transporter GLT-1 determines susceptibility to spreading depression in the mouse cerebral cortex. Glia 68(12):2631-2642 |
| abstractText | Cortical spreading depression (CSD) is a pathological neural excitation that underlies migraine pathophysiology. Since glutamate receptor antagonists impair CSD propagation, susceptibility to CSD might be determined by any of the neuronal (excitatory amino acid carrier 1 [EAAC1]) and glial (GLutamate ASpartate Transporter [GLAST] and glial glutamate transporter 1 [GLT-1]) glutamate transporters, which are responsible for clearing extracellular glutamate. To investigate this hypothesis, we performed electrophysiological, hemodynamic, and electrochemical analyses using EAAC1- (EAAC1 KO), GLAST- (GLAST KO), and conditional GLT1-1-knockout mice (GLT-1 cKO) to assess altered susceptibility to CSD. Despite the incomplete deletion of the gene in the cerebral cortex, GLT-1 cKO mice exhibited significant reduction of GLT-1 protein in the brain without apparent alteration of the cytoarchitecture in the cerebral cortex. Physiological analysis revealed that GLT-1 cKO showed enhanced susceptibility to CSD elicited by chemical stimulation with increased CSD frequency and velocity compared to GLT-1 control. In contrast, the germ-line EAAC1 and GLAST KOs showed no such effect. Intriguingly, both field potential and cerebral blood flow showed faster dynamics with narrower CSD than the controls. An enzyme-based biosensor revealed more rapid accumulation of glutamate in the extracellular space in GLT-1 cKO mice during the early phase of CSD than in GLT-1 control, resulting in an increased susceptibility to CSD. These results provided the first evidence for a novel role of GLT-1 in determining susceptibility to CSD. |
