Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator Richard L Huganir,   Johns Hopkins University; HHMI

Description
Mice that are heterozygous for the synaptic Ras GTPase activating protein 1 homolog targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Homozygotes die in the first week after birth due to severe sensory deficit. Heterozygotes show partial deficits in synaptic plasticity. No gene product (protein) is detected by Western blot analysis of the brain isolated from homozygous animals. This strain may be useful in studies of neurodevelopment, glutamate receptor trafficking and the induction of long-term potentiation (LTP).

Development
Exons 7 and 8 were replaced with a neomycin resistance cassette. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1- Kitl⁺-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed once to C57BL/6J mice. This strain was maintained on a mixed C57BL/6J and 129 genetic background by the donating laboratory.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Mental Retardation, Autosomal Dominant 5; MRD5   (SYNGAP1)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Syngap1^tm1Rlh/Syngap1⁺

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• nervous system phenotype
• reduced long term potentiation
  • long term potentiation induced by TBS was significantly decreased in the CA1 region of hippocampal slices, however there was no difference in the magnitude of long term depression   (MGI Ref ID J:97391)

Syngap1^tm1Rlh/Syngap1^tm1Rlh

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• mortality/aging
• complete postnatal lethality
  • pups die between P5 and P7   (MGI Ref ID J:97391)
• growth/size phenotype
• decreased body size
  • between P4 and P6, pups stay small in size   (MGI Ref ID J:97391)
• behavior/neurological phenotype
• abnormal suckling behavior
  • by P3, pups do not feed from the mother   (MGI Ref ID J:97391)
• bradykinesia
  • by P3, homozygous mutants show less movement   (MGI Ref ID J:97391)
• nervous system phenotype
• abnormal neuron morphology
  • homozygotes had significantly fewer morphological silent synapses (synapses that contain NMDA receptors but not AMPA receptors) and had a greater number of AMPA receptor clusters in cortical neuronal cultures   (MGI Ref ID J:97391)
• decreased brain size   (MGI Ref ID J:97391)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Syngap1^tm1Rlh/Syngap1⁺

        involves: 129S1/Sv * 129X1/SvJ

• nervous system phenotype
• *normal* nervous system phenotype
  • at P14, mice exhibit normal medial perforant path release probability and intrinsic spiking of dentate gyrus neurons   (MGI Ref ID J:193208)
• • abnormal CNS synaptic transmission
    • photosimulation-evoked signals originating in the dentate gyrus are amplified as they spread through the hippocampus unlike in wild-type mice   (MGI Ref ID J:193208)
    • synaptic transmission in the Schaeffer Collateral pathway in the CA1 is strong during early development compared with wild-type mice   (MGI Ref ID J:193208)
    • however, synaptic transmission in the Schaeffer Collateral pathway in the CA1 in adult mice is normal   (MGI Ref ID J:193208)
  • • abnormal excitatory postsynaptic potential
      • by P14, field excitatory postsynaptic potential is increased compared to in control mice   (MGI Ref ID J:193208)
      • however, synaptic function at P9, P21 and later is normal   (MGI Ref ID J:193208)
    • abnormal glutamate-mediated receptor currents
      • at P14, mice exhibit an increase in the ratio of AMPA/NMDA currents in dentate gyrus granule neurons compared with wild-type mice   (MGI Ref ID J:193208)
      • however, NMDAR-evoked synaptic transmission is normal   (MGI Ref ID J:193208)
    • • enhanced AMPA-mediated synaptic currents
        • increased sensitivity at P14   (MGI Ref ID J:193208)
    • abnormal miniature excitatory postsynaptic currents
      • increased amplitude and frequency at P14   (MGI Ref ID J:193208)
      • however, both are normal at P21   (MGI Ref ID J:193208)
    • abnormal miniature inhibitory postsynaptic currents
      • increased frequency and amplitude in the dentate gyrus neurons   (MGI Ref ID J:193208)
  • abnormal dendrite morphology
    • at P14, dentate gyrus neuron dendritic trees exhibit a decrease in the spatial volume compared with in wild-type mice   (MGI Ref ID J:193208)
  • • abnormal dendritic spine morphology
      • larger spines by P14 and persisting into adulthood   (MGI Ref ID J:193208)
      • more mushroom-type spines and fewer stubby spines beginning in the second postnatal week   (MGI Ref ID J:193208)
      • spines are less motile at P14   (MGI Ref ID J:193208)
      • some spines exhibit a spontaneous increase in head volume   (MGI Ref ID J:193208)
      • however, spine density is normal   (MGI Ref ID J:193208)
  • audiogenic seizures   (MGI Ref ID J:193208)
  • increased susceptibility to pharmacologically induced seizures
    • fluorothyl-induced   (MGI Ref ID J:193208)
• behavior/neurological phenotype
• *normal* behavior/neurological phenotype
  • mice exhibit normal contextual fear memory   (MGI Ref ID J:193208)
• • abnormal discrimination learning
    • mice are unable to discriminate between two contexts during contextual fear training unlike wild-type mice   (MGI Ref ID J:193208)
  • audiogenic seizures   (MGI Ref ID J:193208)
  • hyperactivity
    • in an open field at P14   (MGI Ref ID J:193208)
  • increased susceptibility to pharmacologically induced seizures
    • fluorothyl-induced   (MGI Ref ID J:193208)

View Research Applications

Research Applications

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

Developmental Biology Research
Postnatal Lethality
      Homozygous

Neurobiology Research
Neurodevelopmental Defects
Receptor Defects
      glutamate receptor: NMDA

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Syngap1tm1Rlh
Allele Name		targeted mutation 1, Richard L Huganir
Allele Type		Targeted (knock-out)
Mutation Made By		Richard Huganir,   Johns Hopkins University; HHMI
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Syngap1, synaptic Ras GTPase activating protein 1 homolog (rat)
Chromosome		17
Gene Common Name(s)		Gm1963; MRD5; RASA1; RASA5; SYNGAP; gene model 1963, (NCBI);
Molecular Note		To eliminate all possible splice variants, exon 7, which contains the first common methionine present in the shortest splice variant, as well as exon 8, which encodes part of the C2 domain, were replaced with a neomycin resistance gene placed in the opposite orientation. Immunoblot of brain homogenates at P5 demonstrated that protein is abolished in mutants. Overexposure of the immunoblot showed a smear present at less than 2% of wild-type levels, likely made up of protein products resulting from cryptic start sites downstream of the deleted sequence. [MGI Ref ID J:97391]

Genotyping

Genotyping Information

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Kim JH; Lee HK; Takamiya K; Huganir RL. 2003. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. J Neurosci 23(4):1119-24. [PubMed: 12598599]  [MGI Ref ID J:97391]

Additional References

Syngap1^tm1Rlh related

Clement JP; Aceti M; Creson TK; Ozkan ED; Shi Y; Reish NJ; Almonte AG; Miller BH; Wiltgen BJ; Miller CA; Xu X; Rumbaugh G. 2012. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151(4):709-23. [PubMed: 23141534]  [MGI Ref ID J:193208]

Guo X; Hamilton PJ; Reish NJ; Sweatt JD; Miller CA; Rumbaugh G. 2009. Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of Schizophrenia. Neuropsychopharmacology 34(7):1659-72. [PubMed: 19145222]  [MGI Ref ID J:194146]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & Husbandry	When maintained as a live colony, heterozygotes may be bred. Homozygotes die within a week of birth. Backcrossing further to C57BL/6 may reduce viability even more.

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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.

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