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Home  > Press Release  > Glial glutamate transporter GLT-1 determines susceptibility to spreading depression in the mouse cerebral cortex

Glial glutamate transporter GLT-1 determines susceptibility to spreading depression in the mouse cerebral cortex

Abstract

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.

Journal Article

JOURNAL:
GLIA

TITLE:
Glial glutamate transporter GLT-1 determines susceptibility to spreading depression in the mouse cerebral cortex

DOI:
https://doi.org/10.1002/glia.23874

Correspondence to

Kohichi TANAKA, MD, Ph.D, Professor
Department of Molecular Neuroscience,
Medical Research Institute,
Tokyo Medical and Dental University(TMDU)
E-mail:tanaka.aud (at) mri.tmd.ac.jp


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