Mice that are homozygous for the targeted mutation are viable, normal in size and do not display any gross physical or behavioral abnormalities. In heterozygote crosses, the number of homozygous progeny born (15%) does not reach the expected Mendelian ratio indicating low survival of homozygous embryos. No gene product (mRNA or alpha and delta isoform proteins) is detected. The beta isoform gene product is up regulated. cAMP response element modulation protein expression is up regulated 2- to 3-fold. Although fear conditioning and Morris water maze testing demonstrate that homozygous mice have normal learning and short-term memory, long-term memory for cued and contextual conditioning is disrupted. Electrophysiological analysis of the hippocampus of mutant mice reveals abnormal long-term potentiation, which decays to baseline within 90 minutes, whereas wildtype controls display no decay. The long-term memory deficit exhibited by mutant mice can be overcome by additional spaced (10-60 minutes between trials) training. Homozygous mutant mice treated with chronic morphine administration exhibit reduced opiate tolerance and diminished morphine withdrawal. This mutant mouse strain may be useful in studies related to the molecular mechanisms of long-term memory and in studies related to the chronic effects of drug abuse.
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 2. The construct was electroporated into 129S2/SvPas derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts.
|Allele Name||targeted mutation 1, Gunther Schutz|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||CREB -; CREBalphadelta; CREBalphadelta-; CREBalphadelta|
|Gene Symbol and Name||Creb1, cAMP responsive element binding protein 1|
|Strain of Origin||129S2/SvPas|
|Molecular Note||A promoterless neomycin resistance gene was inserted in frame into exon 2. RNase protection assays on RNA derived from liver of homozyogous mice demonstrated that no detectable alpha or delta isoform transcript was produced from this allele; however, a beta isoform transcript is upregulated (J:31886). Western blot analysis on liver extracts from homozygous mice confirmed that no alpha or delta isoform of the encoded protein was produced.|
|Mutations Made By|| |
Maress Lacuesta, University of California, Los Angeles
The resulting chimeric animals were crossed to C57BL/6 mice, and then backcrossed to C57BL/6 for 7 generations. In heterozygote crosses, the number of homozygous progeny born (15%) does not reach the expected Mendelian ratio indicating low survival of homozygous embryos. The strain is maintained as a heterozygote.
When using the B6.129S2-Creb1tm1Gsc/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #004445 in your Materials and Methods section.