title: Astrocyte-mediated infantile-onset leukoencephalopathy mouse model.
abstract: Astrocytes have recently been shown to provide physiological support for various brain functions, although little is known about their involvement in white matter integrity. Several inherited infantile-onset leukoencephalopathies, such as Alexander disease and megalencephalic leukoencephalopathy with subcortical cysts (MLC), implicate astrocytic involvement in the formation of white matter. Several mouse models of MLC had been generated by knocking out the Mlc1 gene; however, none of those models was reported to show myelin abnormalities prior to formation of the myelin sheath. Here we generated a new Mlc1 knockout mouse and a Mlc1 overexpressing mouse, and demonstrate that astrocyte-specific Mlc1 overexpression causes infantile-onset abnormalities of the white matter in which astrocytic swelling followed by myelin membrane splitting are present, whereas knocking out Mlc1 does not, and only shows myelin abnormalities after 12 months of age. Biochemical analyses demonstrated that MLC1 interacts with the Na+/K+ATPase and that overexpression of Mlc1 results in decreased activity of the astrocytic Na+/K+pump. In contrast, no changes in Na+/K+pump activity were observed in Mlc1 KO mice, suggesting that the reduction in Na+/K+pump activity resulting from Mlc1 overexpression causes astrocytic swelling. Our infantile-onset leukoencephalopathy model based on Mlc1 overexpression may provide an opportunity to further explore the roles of astrocytes in white matter development and structural integrity. We established a novel mouse model for infantile-onset leukoencephalopathy by the overexpression of Mlc1. Mlc1 overexpression reduced activity of the astrocytic sodium pump, which may underlie white matter edema followed by myelin membrane splitting. GLIA 2016 GLIA 2017;65:150-168.
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.|Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, 444-8787, Japan.
authors.forename: Shouta
authors.initials: S
authors.lastname: Sugio
authors.affiliation: Department of Physiology School of Dentistry, The Center of EM and Bio-Imaging Research, Nano-Neuroanatomy, Iwate Medical University, Morioka, 020-8505, Japan.
authors.forename: Koujiro
authors.initials: K
authors.lastname: Tohyama
authors.affiliation: Division of Membrane Physiology, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Oku
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.|Department of Orthopedic Surgery, National Hospital Organization, Murayama Medical Center, Tokyo, 208-0011, Japan.
authors.forename: Kanehiro
authors.initials: K
authors.lastname: Fujiyoshi
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.|Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, 444-8787, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, 160-8582, Japan.|Central Institute for Experimental Animals, Kawasaki, 210-0821, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Hikishima
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Yano
authors.affiliation: Division of Neuropathology, Department of Pathology, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, 444-8787, Japan.|Division of Membrane Physiology, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukata
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.|Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, 444-8787, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikenaka
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.|Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Kenji F
authors.initials: KF
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003560:Cysts / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D066127:White Matter / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C498927:Mlc1 protein, mouse
keywords: Mlc1; Na+/K+ ATPase; astrocytic swelling; myelin membrane splitting; white matter