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.

A functional variant in SLC1A3 influences ADHD risk by disrupting a hsa‐miR‐3171 binding site: A two‐stage association study

“…Besides, it is reported that duplications of SLC1A3 was associated with ADHD, and behavioral problems resembling ADHD are observed, which is in line with the glial glutamate transporter role of SLC1A3 . These studies support the involvement of the 5p13 region in ADHD, the single region of overlap in a pooled analysis of US and Dutch genome‐wide linkage data . However, Nancy et al failed to replicate the association between SLC1A3 (rs3776581, rs2269272 and rs2032893) and ADHD .…”

“…33 These studies support the involvement of the 5p13 region in ADHD, the single region of overlap in a pooled analysis of US and Dutch genome-wide linkage data. 34 However, Nancy et al failed to…”

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

“…Using the Analyze Skeleton plugin of Image J software, spines densities were analyzed in random selected distal branches between 10 and 20 μm in length. Spine morphology analysis was performed as previously described with some changes (Miyoshi et al, 2014) (See Supplemental Information). …”

The Architecture of GluD2 Ionotropic Delta Glutamate Receptor Elucidated by cryo-EM

“…Notably, GluD2 is associated with autism spectrum disorder, schizophrenia, cerebellar ataxia, intellectual disability, attention deficit hyperactivity disorder, and motor and cognitive deficit disorders (Kashiwabuchi et al, 1995;Kondo et al, 2005;Katoh et al, 2005;Utine et al, 2013;Miyoshi et al, 2014).…”