129S-Slc6a4^tm2.1Rbl/JvvwJ

Stock number: 039968
Product name: SERT Ala56
Research areas: Neurobiology Research, Research Tools

Description

SERT Ala56 mice have an alanine to glycine mutation at position 56 (G56A) in exon 2 of the Slc6a4 gene, analogous to a mutation found in patients diagnosed with autism spectrum disorders (ASDs) and obsessive-compulsive disorder (OCD). This strain may be useful for studying the effects of altered serotonin homeostasis on the risk of ASDs and OCD development.

Detailed description

SERT Ala56 mice have a mutation in exon 2 of the solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (Slc6a4) gene. Specifically, an glycine to alanine mutation was created at position 56 (G56A), analogous to a mutation found in patients diagnosed with autism spectrum disorders (ASDs) and obsessive-compulsive disorder (OCD).

Slc6a4 encodes the serotonin transporter (SERT) which regulates the release of the neurotransmitter, serotonin (5-HT). The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. SERT has been implicated in several disorders, including autism, schizophrenia, clinical depression, obsessive-compulsive disorder (OCD), and other neuropsychiatric disorders. ASD is a male-predominant disorder that is characterized by deficits in social interactions and communication, as well as repetitive behavior. Hyperserotonemia is a well replicated biomarker that is present in approximately 30% of patients with ASD.

These SERT Ala56 mice exhibit normal growth and fertility. They display a significant increase in CNS 5-HT clearance, enhanced 5-HT receptor sensitivity, and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT1A and 5HT2A receptor hypersensitivity. SERT Ala56 mice also display alterations in a number of ASD-relevant behaviors such as social function, communication, and repetitive behavior.

Homozygous mice are viable and fertile. The donating investigator reports that maternal genotype affects offspring development. They suggest breeding heterozygous females to heterozygous males to produce homozygous offspring. A two amino acid, functional haplotype exists in the Slc6a4 coding sequence between C57BL/6 and most other strains, including 129. As such, any backcrossing with a strain other than 129 may result in a wildtype Slc6a4 allele not derived from 129 that may produce an aberrant phenotype.

Of note, SERT M172 (Stock No. 040026) is a similar strain, with a I172M mutation in exon 4, and exhibit loss of high-affinity recognition of multiple antidepressants and cocaine without an impact on basal 5-HT transport. SERT M172 mice are useful for studying the mood regulating actions of 5-HT in the CNS and in the development of new antidepressant therapies.

Development

The SERT Ala56 targeting vector was designed to create a mutation in exon 2 of the solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (Slc6a4) gene. Specifically, an glycine to alanine mutation was created at position 56 (G56A), analogous to a mutation found in patients diagnosed with autism spectrum disorders (ASDs) and obsessive-compulsive disorder (OCD). A loxP-flanked neomycin resistance (neo) cassette was inserted downstream of exon 4. The construct was electroporated into 129S6/SvEvTac-derived embryonic stem (ES) cells and correctly targeted ES cells were injected into blastocysts. Resulting mice were bred to Prm-cre transgenic mice on a 129S genetic background (similar to Stock No. 003328) to remove the selection cassette. SERT Ala56 mice were bred to 129S6 mice and were maintained on this background by the donating laboratory. Upon arrival at The Jackson Laboratory, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize 129S1/SvImJ oocytes (Stock No. 002448).

Allele

Symbol: Slc6a4^tm2.1Rbl
Name: targeted mutation 2.1, Randy D Blakely
MGI accession ID: MGI:5521182
Generation method: Targeted
Attributes: Humanized sequence
Synonyms: SERT Ala56; Slc6a4 56Ala
Marker symbol: Slc6a4
Marker name: solute carrier family 6 (neurotransmitter transporter, serotonin), member 4
Marker synonyms: 5HTT; 5-HTT; 5-HTTLPR; hSERT; Htt; OCD1; SERT; SERT1
Chromosome: 11
Strain of origin: 129S6/SvEvTac
Molecular note: A targeted mutation in exon 2 resulted in the amino acid substitution of glycine for alanine at position 56 (G56A). Cre-mediated recombination removed the floxed neomycin resistance cassette inserted downstream of exon 4.
General note: This allele represents an autism spectrum disorder (ASD) susceptibility variant, rather than a highly penetrant, monogenic cause of ASD and mice are not expected to model all aspects of ASD (J:202876).