Description

Strain Information

Former Names B6.Cg-Cntnap2tm1Pele/J    (Changed: 17-JAN-12 ) Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Heterozygote x Heterozygote         (Female x Male)   09-FEB-12 Species laboratory mouse Generation N11+F3(or N3) (23-APR-12) Generation Definitions   Donating Investigator Elior Peles,   Weizmann Institute of Science

Description
No gene product (mRNA or protein) is detected by RT-PCR, Western blot, or immunoprecipitation analysis of brain tissue from homozygous Cntnap2 (contactin associated protein-like 2) knockout animals. Homozygous mice older than 6 months of age exhibit handling-induced and spontaneous seizures. Abnormal organization of neurons in the cortex and fewer parvalbumin-positive interneurons in the hippocampus are observed in homozygotes. Homozygotes exhibit an asynchronous neuronal firing pattern, but no defects in peripheral and central nerve conductance. Homozygotes also display hyperreactivity in open field tests and to thermal sensory stimuli. In buried food olfaction analysis, homozygotes perform better than wildtype controls. Fewer ultrasonic vocalizations are observed in homozygous pups. Mutant mice exhibit impaired social behavior: less interaction, increased grooming and digging, impaired nest building. Risperidone (atypical antipsychotic drug) treatment reduced the phenotype severity of mutant mice. Contactin associated protein-like 2, a member of the neurexin superfamily, is critical for proper potassium ion channel localization in myelinated axons at the juxtaparanodal region. Mutations in human CNTNAP2 have been found to play a role in cortical dysplasia-focal epilepsy syndrome and autism spectrum disorders. Mice that are homozygous for this targeted mutation are viable, fertile, and normal in size.

Development
A targeting vector containing the neomycin resistance gene was used to disrupt exon 1. The construct was electroporated into 129 derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were used to generate chimeric animals via aggregation. The resulting chimeric animals were crossed to ICR mice, and then crossed to 129/SvEv and C57BL/6J. The mice were then backcrossed to C57BL/6J for more than 10 generations. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Cortical Dysplasia-Focal Epilepsy Syndrome

- Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Autism

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Autism, Susceptibility to, 15; AUTS15   (CNTNAP2)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Cntnap2^tm1Pele/Cntnap2^tm1Pele

        B6.129-Cntnap2^tm1Pele

• behavior/neurological phenotype
• *normal* behavior/neurological phenotype
  • no differences are seen in the light-dark exploration test between mutants and wild-type mice   (MGI Ref ID J:177110)
  • mutants treated with the drug Risperidone exhibit rescue of the hyperactivity, repetitive behavior/perseveration and nesting deficits   (MGI Ref ID J:177110)
• • abnormal motor coordination/ balance
    • mutants perform better than wild-type mice on the rotorod   (MGI Ref ID J:177110)
  • abnormal nest building behavior
    • mutants are impaired in nest-building behavior, scoring less than half of the wild-type criterion   (MGI Ref ID J:177110)
    • mutants treated with the drug Risperidone exhibit rescue of the nesting deficits   (MGI Ref ID J:177110)
  • abnormal spatial learning
    • mutants perform similarly to wild-type mice in the Morris water maze probe trials, however in a classic reversal task using the Morris water maze, mutants show impaired learning of the new location of the platform and perform poorly in the probe test   (MGI Ref ID J:177110)
  • abnormal vocalization
    • mutants emit a lower number of ultrasonic calls than wild-type mice at all ages   (MGI Ref ID J:177110)
  • decreased thermal nociceptive threshold
    • mutants exhibit hyperreactivity to thermal sensory stimuli   (MGI Ref ID J:177110)
    • however, no differences seen in the acoustic startle response or prepulse inhibition   (MGI Ref ID J:177110)
  • hyperactivity
    • mutants show greater locomotor activity than wild-type mice in the open field test   (MGI Ref ID J:177110)
    • mutants treated with the drug Risperidone exhibit rescue of the hyperactivity   (MGI Ref ID J:177110)
  • increased grooming behavior
    • mutants spend almost 3 times more time grooming than wild-type mice   (MGI Ref ID J:177110)
  • increased stereotypic behavior
    • in the spontaneous alternation T maze test, mutants show higher number of no alternations in a standard 10 trial test, indicating preservation   (MGI Ref ID J:177110)
    • mutants treated with the drug Risperidone exhibit rescue of the repetitive behavior/perseveration   (MGI Ref ID J:177110)
  • seizures
    • mutants older than 6 months of age commonly exhibit spontaneous seizures   (MGI Ref ID J:177110)
  • • environmentally induced seizures
      • seizures are induced by mild stressors during routine handling   (MGI Ref ID J:177110)
  • social withdrawal
    • in a juvenile play test, mutants at P21 spend less time interacting with each other and instead show increased repetitive behaviors such as grooming and digging   (MGI Ref ID J:177110)
    • in a three-chamber social interaction test in adults, mutants do not show a preference for the cup with a mouse as seen in wild-type mice   (MGI Ref ID J:177110)
• integument phenotype
• decreased thermal nociceptive threshold
  • mutants exhibit hyperreactivity to thermal sensory stimuli   (MGI Ref ID J:177110)
  • however, no differences seen in the acoustic startle response or prepulse inhibition   (MGI Ref ID J:177110)
• nervous system phenotype
• abnormal brain interneuron morphology
  • mutants exhibit a reduction in parvalbumin+ interneurons in the hippocampus   (MGI Ref ID J:177110)
  • mutants exhibit a decrease in the number of GABAergic interneurons in all laminae and in the striatum   (MGI Ref ID J:177110)
• abnormal brain wave pattern
  • at 8 months of age, freely moving mutants exhibit generalized interictal spike discharges during slow-wave sleep   (MGI Ref ID J:177110)
• abnormal corpus callosum morphology
  • ectopic neurons are seen in the corpus callosum of mutants at P14; ectopic neurons are seen through adulthood   (MGI Ref ID J:177110)
• abnormal neuron physiology
  • mutants exhibit reduced cortical neuronal synchrony as indicated by two-photon calcium imaging of layer II/III neurons from somatosensory cortex showing that neuronal firing pattern is highly asynchronous compared to wild-type mice   (MGI Ref ID J:177110)
  • however, neither the average firing amplitude nor the average firing rate are changed, suggesting that the defect is due to a network dysfunction rather than abnormalities in neuronal activity or conduction per se   (MGI Ref ID J:177110)
• • abnormal neuronal migration
    • ectopic neurons are seen in the corpus callosum of mutants at P14   (MGI Ref ID J:177110)
    • mutants exhibit abnormal migration of cortical projection neurons as evidenced by the higher numbers of CUX1+ cells in deep cortical layers   (MGI Ref ID J:177110)
• astrocytosis
  • reactive astrocytosis is seen throughout the hippocampus after onset of seizures, especially in the hilus   (MGI Ref ID J:177110)
  • however, neuronal loss is not seen in the hippocampus   (MGI Ref ID J:177110)
• seizures
  • mutants older than 6 months of age commonly exhibit spontaneous seizures   (MGI Ref ID J:177110)
• • environmentally induced seizures
    • seizures are induced by mild stressors during routine handling   (MGI Ref ID J:177110)
• taste/olfaction phenotype
• abnormal olfaction
  • mutants perform better than wild-type mice in the buried food test, indicating better olfaction   (MGI Ref ID J:177110)
• cellular phenotype
• abnormal neuronal migration
  • ectopic neurons are seen in the corpus callosum of mutants at P14   (MGI Ref ID J:177110)
  • mutants exhibit abnormal migration of cortical projection neurons as evidenced by the higher numbers of CUX1+ cells in deep cortical layers   (MGI Ref ID J:177110)

View Research Applications

Research Applications

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

Developmental Biology Research
Neurodevelopmental Defects

Mouse/Human Gene Homologs
Epilepsy

Neurobiology Research
Behavioral and Learning Defects
      high anxiety
Epilepsy
Neurodevelopmental Defects
      Autism

Research Tools
Neurobiology Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Cntnap2tm1Pele
Allele Name		targeted mutation 1, Elior Peles
Allele Type		Targeted (knock-out)
Common Name(s)		Caspr2-;
Mutation Made By		Elior Peles,   Weizmann Institute of Science
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Cntnap2, contactin associated protein-like 2
Chromosome		6
Gene Common Name(s)		5430425M22Rik; AUTS15; CASPR2; CDFE; NRXN4; PTHSL1; RIKEN cDNA 5430425M22 gene; mKIAA0868;
Molecular Note		Exon 1, which contains the start codon encodes the signal peptide, was replaced with a neomycin selection cassette inserted by homologous recombination. Transcript was undetected by RT-PCR analysis of homozygous mutant brain RNA. Protein was undetected in the central nervous system of homozygous mutant mice by immunoprecipitation and Western blot analysis. Similarly, no specific staining was observed by immunolabeling of sciatic nerve tissue. [MGI Ref ID J:85502]

Genotyping

Genotyping Information

Genotyping Protocols

Cntnap2^tm1Pele-alternate1, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Poliak S; Salomon D; Elhanany H; Sabanay H; Kiernan B; Pevny L; Stewart CL; Xu X; Chiu SY; Shrager P; Furley AJ; Peles E. 2003. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol 162(6):1149-60. [PubMed: 12963709]  [MGI Ref ID J:85502]

Additional References

Cntnap2^tm1Pele related

Horresh I; Bar V; Kissil JL; Peles E. 2010. Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. J Neurosci 30(7):2480-9. [PubMed: 20164332]  [MGI Ref ID J:157838]

Horresh I; Poliak S; Grant S; Bredt D; Rasband MN; Peles E. 2008. Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons. J Neurosci 28(52):14213-22. [PubMed: 19109503]  [MGI Ref ID J:143878]

Ogawa Y; Horresh I; Trimmer JS; Bredt DS; Peles E; Rasband MN. 2008. Postsynaptic density-93 clusters Kv1 channels at axon initial segments independently of Caspr2. J Neurosci 28(22):5731-9. [PubMed: 18509034]  [MGI Ref ID J:149503]

Ogawa Y; Oses-Prieto J; Kim MY; Horresh I; Peles E; Burlingame AL; Trimmer JS; Meijer D; Rasband MN. 2010. ADAM22, a Kv1 channel-interacting protein, recruits membrane-associated guanylate kinases to juxtaparanodes of myelinated axons. J Neurosci 30(3):1038-48. [PubMed: 20089912]  [MGI Ref ID J:157696]

Ogawa Y; Schafer DP; Horresh I; Bar V; Hales K; Yang Y; Susuki K; Peles E; Stankewich MC; Rasband MN. 2006. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton. J Neurosci 26(19):5230-9. [PubMed: 16687515]  [MGI Ref ID J:108683]

Penagarikano O; Abrahams BS; Herman EI; Winden KD; Gdalyahu A; Dong H; Sonnenblick LI; Gruver R; Almajano J; Bragin A; Golshani P; Trachtenberg JT; Peles E; Geschwind DH. 2011. Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits. Cell 147(1):235-46. [PubMed: 21962519]  [MGI Ref ID J:177110]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX18

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes. Homozygotes older than 6 months can have spontaneous seizures and seizures induced by mild stress, such as handling.
Mating System	Heterozygote x Heterozygote         (Female x Male)   09-FEB-12
Diet Information	LabDiet® 5K20

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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