title: Sustained down-regulation of β-dystroglycan and associated dysfunctions of astrocytic endfeet in epileptic cerebral cortex.
abstract: Epilepsy is characterized by the abnormal activation of neurons in the cerebral cortex, but the molecular and cellular mechanisms contributing to the development of recurrent seizures are largely unknown. Recently, the critical involvement of astrocytes in the pathophysiology of epilepsy has been proposed. However, the nature of plastic modulations of astrocytic proteins in the epileptic cortex remains poorly understood. In this study, we utilized the zero magnesium in vitro model of epilepsy and examined the potential molecular changes of cortical astrocytes, focusing specifically on endfeet, where specialized biochemical compartments exist. We find that the continuous epileptic activation of neurons for 1 h decreases the expression level of β-dystroglycan (βDG) in acute cortical brain slices prepared from mice. This change is completely abolished by the pharmacological blockade of NMDA-type glutamate receptors as well as by matrix metalloproteinase inhibitors. Consistent with the highly specialized localization of βDG at astrocytic endfeet, where it plays a pivotal role in anchoring endfeet-enriched proteins in astrocytes, the down-regulation of βDG is accompanied by a decrease in the expression of AQP4 but not laminin. Importantly, this down-regulation of βDG persists for at least 1 h, even after the apparent recovery of neuronal activation. Finally, we show that the down-regulation of βDG is associated with the dysfunction of the endfeet at the blood-brain interface as a diffusion barrier. These results suggest that the sustained down-regulation of βDG leads to dysfunctions of astrocytic endfeet in the epileptic cerebral cortex and may contribute to the pathogenesis of epilepsy.
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan,; Department of Nephrology and Dialysis, Tokyo Medical University, Tokyo 160-0023, Japan, and.
authors.forename: Asako
authors.initials: A
authors.lastname: Gondo
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Shinotsuka
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan,; College of Engineering and Yokohama National University, Kanagawa 240-8501, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Morita
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Abe
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yasui
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan,; Graduate School of Environment and Information Sciences, Yokohama National University, Kanagawa 240-8501, Japan. Electronic address: mnuriya@z2.keio.jp.
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Nuriya
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier; D020013:Calcium Signaling; D002540:Cerebral Cortex / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation; D049030:Dystroglycans / Q000378:metabolism*; D004827:Epilepsy / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D007797:Laminin / Q000378:metabolism; D008274:Magnesium / Q000502:physiology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D021381:Protein Transport
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D007797:Laminin; D049030:Dystroglycans; D020782:Matrix Metalloproteinases; D008274:Magnesium
keywords: AQP4; Astrocyte; Brain Slice; Cerebral Cortex; Dystroglycan; Endfeet; Epilepsy; Molecular Cell Biology; Pathogenesis; Protein Degradation