Overview

These Creb1 knock-out mice exhibit long-term memory deficit.

Donating Investigator

Alcino J. Silva, University of California, Los Angeles

Genetic overview

Genetic Background	Generation

Creb1^tm1Gsc

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Creb1	cAMP responsive element binding protein 1

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Research Applications

Neurobiology Research
Developmental Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

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.

Development

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.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Bourtchuladze R; Frenguelli B; Blendy J; Cioffi D; Schutz G; Silva AJ. 1994. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79(1):59-68PubMed: 7923378 MGI: J:20672

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Genetics

Creb1^tm1Gsc

Allele Symbol: Creb1^tm1Gsc

Allele Name	targeted mutation 1, Gunther Schutz
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	CREB -; CREB^alphadelta; CREB^alphadelta-; CREBalphadelta
Gene Symbol and Name	Creb1, cAMP responsive element binding protein 1
Gene Synonym(s)
Strain of Origin	129S2/SvPas
Chromosome	1
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

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Creb1^tm1Gsc related

Neurobiology Research
- Behavioral and Learning Defects
Developmental Biology Research
- Embryonic Lethality (Homozygous)
  - incomplete

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Creb1^tm1Gsc/Creb1^tm1Gsc
involves: 129S2/SvPas

mortality/aging

decreased survivor rate
- Normal - however, surviving mice exhibit normal histology and morphology
- fewer than expected mice survive to adulthood (15% compared to an expected 25%)

postnatal lethality
- fewer than expected mice survive to adulthood (15% compared to an expected 25%)
- Normal - however, surviving mice exhibit normal histology and morphology

nervous system phenotype

abnormal CNS synaptic transmission
- the ratio of field excitatory postsynaptic potential slope to fiber volley in untetanized hippocampal slices is increased 1.6-fold compared to in wild-type slices
- Normal - however, paired pulse facilitation is normal

reduced long term potentiation
- long term potentiation decays to baseline 90 minutes after tetanus unlike in wild-type mice that maintain stable LTP for 2 hours
- despite normal peak posttetanic potentiation, synaptic potentiation is lower than in wild-type mice as early as 10 minutes after titanic conditioning

abnormal stellate ganglion morphology
- stellate ganglion is larger than in controls at E17.5

small superior cervical ganglion
- SCG is smaller than in controls at E17.5

behavior/neurological phenotype

abnormal cued conditioning behavior
- mice receiving extra training still perform worse than wild-type mice
- 2 and 24 hours after cued conditioning, all but 2 mice exhibit reduced freezing compared to wild-type mice
- Normal - however, cued conditioning after 30 and 60 minutes is normal

abnormal temporal memory
- regardless of additional training, mice exhibit defects in long-term memory following contextual and cued conditioning compared to wild-type mice

abnormal contextual conditioning behavior
- mice receiving extra training still perform worse than wild-type mice
- 60 minutes and 24 hours after contextual conditioning, all but 1 mouse exhibit reduced freezing compared to wild-type mice
- Normal - however, contextual conditioning 30 minutes after conditioning is normal

decreased behavioral withdrawal response
- following treatment with naloxone, mice chronically treated with morphine exhibit reduced withdrawal symptoms with no signs of sniffing or pstosis compared to similarly treated wild-type mice

abnormal behavioral response to addictive substance
- at high doses, mice develop a tolerance to morphine analgesia compared to wild-type mice

abnormal spatial learning
- while intensive training improves performance, mice perform worse than wild-type mice in a Morris water maze

decreased vertical activity

References

Bourtchuladze R; Frenguelli B; Blendy J; Cioffi D; Schutz G; Silva AJ. 1994. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79(1):59-68PubMed: 7923378 MGI: J:20672

Additional References

Hummler E; Cole TJ; Blendy JA; Ganss R; Aguzzi A; Schmid W; Beermann F; Schutz G. 1994. Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc Natl Acad Sci U S A 91(12):5647-51PubMed: 8202542 MGI: J:18749
Maldonado R; Blendy JA; Tzavara E; Gass P; Roques BP; Hanoune J; Schutz G. 1996. Reduction of morphine abstinence in mice with a mutation in the gene encoding CREB [see comments] Science 273(5275):657-9PubMed: 8662559 MGI: J:34605

Additional - Creb1^tm1Gsc related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Creb1
- Genotyping resources and troubleshooting
Breeding Considerations

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.
- Additional Breeding and Husbandry Support
Citation
When using the B6.129S2-Creb1^tm1Gsc/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #004445 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or Wild-type for Creb1<tm1Gsc>

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Creb1tm1Gsc

Allele Symbol: Creb1tm1Gsc

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Creb1tm1Gsc related

Mammalian Phenotype Terms by Genotype

Genotype: Creb1tm1Gsc/Creb1tm1Gscinvolves: 129S2/SvPas

mortality/aging

nervous system phenotype

behavior/neurological phenotype

References

Additional References

Additional - Creb1tm1Gsc related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Creb1^tm1Gsc

Allele Symbol: Creb1^tm1Gsc

Genotype: Creb1^tm1Gsc related

Genotype: Creb1^tm1Gsc/Creb1^tm1Gsc
involves: 129S2/SvPas

Additional - Creb1^tm1Gsc related