129S-Slc6a4^tm1.1Rbl/J

Stock number: 040026
Product name: SERT M172
Research areas: Neurobiology Research, Research Tools

Description

SERT M172 mice have a methionine for isoleucine at position 172 (I172M) in exon 4 of the Slc6a4 gene. The I172M mutation in these mice eliminates high-affinity recognition of multiple antidepressants and cocaine without an impact on basal 5-HT transport. This strain may be useful for studying the mood regulating actions of 5-HT in the CNS and in the development of new antidepressant therapies.

Detailed description

SERT M172 mice have a mutation in exon 4 of the solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (Slc6a4) gene. Specifically, a methionine for isoleucine mutation was created at position 172 (I172M) in transmembrane domain 3.

Slc6a4 encodes the sertonin 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 schizophrenia, clinical depression, obsessive-compulsive disorder (OCD), and other neuropsychiatric disorders. SERT is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family.

The I172M mutation in these SERT M172 mice eliminates high-affinity recognition of multiple antidepressants and cocaine without an impact on basal 5-HT transport. Homozygous SERT M172 mice are viable and fertile. They exhibit normal basal SERT protein levels, 5-HT transport rates, and 5-HT levels. However, they display a substantial loss of sensitivity to the selective 5-HT reuptake inhibitors fluoxetine and citalopram, as well as to cocaine.

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 Ala56 (Stock No. 039968) is a similar strain, with a G56A mutation in exon 2, and exhibits an increase in CNS 5-HT clearance and enhanced 5-HT receptor sensitivity. SERT Ala56 mice are useful for studying the effects of altered serotonin homeostasis on the risk of ASDs and OCD development.

Development

The SERT M172 targeting vector was designed to create a mutation in exon 4 of the solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (Slc6a4) gene. Specifically, a methionine for isoleucine mutation was created at position 172 (I172M) in transmembrane domain 3. 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 M172 mice were bred to 129S6 mice and were maintained on this background by the donating laboratory. Cryopreserved sperm was shipped to The Jackson Laboratory. To establish our live colony, an aliquot of frozen sperm was used to fertilize 129S1/SvImJ oocytes (Stock No. 002448).

Allele

Symbol: Slc6a4^tm1.1Rbl
Name: targeted mutation 1.1, Randy D Blakely
MGI accession ID: MGI:4946603
Generation method: Targeted
Attributes: Not Specified
Synonyms: Sert^M172
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: Exon 4 was replaced with a modified one in which nucleotide substitutions result in the amino acid substitution of methionine for isoleucine at position 172 (I172M). A floxed neo cassette inserted downstream of exon 4 was removed by cre-mediated recombination.