B6(Cg)-Grin2b^tm1.1Bcgen/CsbdJ

Stock number: 039026
Product name: Grin2b^C456Y
Research areas: Developmental Biology Research, Neurobiology Research, Research Tools

Description

Grin2b^C456Y mice have a cysteine to tyrosine (C456Y) mutation in exon 6 of the Grin2b gene. This strain may be useful for studying neurodevelopmental and neuropsychiatric disorders.

Detailed description

The targeted glutamate receptor, ionotropic, NMDA2B (epsilon 2) (Grin2b or GluN2B) gene encodes part of the excitatory neurotransmitter N-methyl-D-aspartate (NMDA) receptor (NMDAR). Mutations in this gene have been associated with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), developmental delay, intellectual disability, attention-deficit/hyperactivity disorder (ADHD), epilepsy, schizophrenia, obsessive-compulsive disorder, and encephalopathy. The early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation.

These Grin2b^+/C456Y mice contain a cysteine to tyrosine (C456Y) mutation in exon 6 of Grin2b. This mutation is a de novo mutation identified in a male individual with autism spectrum disorder (ASD) and intellectual disability.



Heterozygous Grin2b^+/C456Y mice show a substantial decrease in GluN2B protein levels. Currents of GluN2B-containing NMDARs and NMDAR-dependent long-term depression (LTD), but not long-term potentiation (LTP), are also decreased. These mice exhibit normal social interaction but enhanced anxiety-like behavior in pups and anxiolytic-like behavior in juveniles and adults. Early, but not late, treatment of young mice (P7-16) with the NMDAR agonist D-cycloserine normalized NMDAR currents and LTD in juvenile Grin2b^+/C456Y mice and improved anxiolytic-like behavior in adult mice.

Homozygous mice are lethal by P7.

Development

A targeting vector was designed to insert a frt-flanked neomycin resistance (neo) cassette downstream of exon 5 of the glutamate receptor, ionotropic, NMDA2B (epsilon 2) (Grin2b) gene. This targeting vector also contains a mutant exon 6, with a cysteine to tyrosine (C456Y) mutation [TGC to TAC], replacing endogenous exon 6. This mutation is a de novo mutation identified in a male individual with autism spectrum disorder (ASD) and intellectual disability. The construct was electroporated into C57BL/6-derived embryonic stem (ES) cells and correctly targeted ES cells were injected into blastocysts. The resulting Grin2b^C456Y mice were bred to Prm1-flp mice on a C57BL/6J background to remove the frt-flanked neo cassette. Mice were further maintained on a C57BL/6J genetic background (Stock No. 000664). Upon arrival at The Jackson Laboratory, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes.

Allele

Symbol: Grin2b^tm1.1Bcgen
Name: targeted mutation 1.1, Biocytogen LLC
MGI accession ID: MGI:7543572
Generation method: Targeted
Attributes: Not Specified
Synonyms: Grin2b^C456Y
Marker symbol: Grin2b
Marker name: glutamate receptor, ionotropic, NMDA2B (epsilon 2)
Marker synonyms: DEE27; EIEE27; GluN2B; GluRepsilon2; hNR3; MRD6; NMDAR2B; NR2B; NR3
Chromosome: 6
Strain of origin: C57BL/6J
Molecular note: The targeting vector introduced an FRT-flanked neomycin resistance cassette into intron 5 and replaced exon 6 with a modified one with the mutation responsible for the amino acid substitution cysteine with tyrosine atposition 456 (C456Y). Flp-mediated recombination removed the selection cassette.