title: A new mouse allele of glutamate receptor delta 2 with cerebellar atrophy and progressive ataxia.
abstract: Spinocerebellar degenerations (SCDs) are a large class of sporadic or hereditary neurodegenerative disorders characterized by progressive motion defects and degenerative changes in the cerebellum and other parts of the CNS. Here we report the identification and establishment from a C57BL/6J mouse colony of a novel mouse line developing spontaneous progressive ataxia, which we refer to as ts3. Frequency of the phenotypic expression was consistent with an autosomal recessive Mendelian trait of inheritance, suggesting that a single gene mutation is responsible for the ataxic phenotype of this line. The onset of ataxia was observed at about three weeks of age, which slowly progressed until the hind limbs became entirely paralyzed in many cases. Micro-MRI study revealed significant cerebellar atrophy in all the ataxic mice, although individual variations were observed. Detailed histological analyses demonstrated significant atrophy of the anterior folia with reduced granule cells (GC) and abnormal morphology of cerebellar Purkinje cells (PC). Study by ultra-high voltage electron microscopy (UHVEM) further indicated aberrant morphology of PC dendrites and their spines, suggesting both morphological and functional abnormalities of the PC in the mutants. Immunohistochemical studies also revealed defects in parallel fiber (PF)-PC synapse formation and abnormal distal extension of climbing fibers (CF). Based on the phenotypic similarities of the ts3 mutant with other known ataxic mutants, we performed immunohistological analyses and found that expression levels of two genes and their products, glutamate receptor delta2 (grid2) and its ligand, cerebellin1 (Cbln1), are significantly reduced or undetectable. Finally, we sequenced the candidate genes and detected a large deletion in the coding region of the grid2 gene. Our present study suggests that ts3 is a new allele of the grid2 gene, which causes similar but different phenotypes as compared to other grid2 mutants.
authors.affiliation: Department of Anatomy and Neurobiology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Miyoshi
authors.affiliation: Biofunctional Imaging Laboratory, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kinuko
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Laboratory of Experimental Animal Models, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Koura
authors.affiliation: Department of Neurology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Saigoh
authors.affiliation: Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, Ibaraki, Osaka, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kajimura
authors.affiliation: Section of Laboratory Equipment, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Monobe
authors.affiliation: Department of Neurology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kusunoki
authors.affiliation: Laboratory of Experimental Animal Models, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Anatomy and Neurobiology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hayasaka
mesh_terms: D000818:Animals; D001259:Ataxia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D001284:Atrophy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis; D011498:Protein Precursors / Q000032:analysis; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D017470:Receptors, Glutamate / Q000032:analysis / Q000235:genetics*
chemical_list: C092370:Cbln1 protein, mouse; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2