Strain Name:

B6;129-Hcn1tm2Kndl/J

Stock Number:

005034

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Mice that are homozygous for the targeted mutation exhibit impaired learning capacity in visible platform swimming water maze task and rotorod test, and abnormal eye blink conditioning response. Purkinje cell electrophysiology is abnormal. This mutant mouse strain may be useful in studies of learning, memory and neurophysiology.

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.
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Specieslaboratory mouse
 
Donating Investigator Eric R Kandel,   Columbia University

Description
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No mRNA encoding the pore/S6 transmembrane domain is detected by in situ hybridization. No HCN1 protein is detected by Western blot analysis of membrane extracts from cerebellum, hippocampus or cortex. Mutant mice exhibit impaired learning capacity in visible platform swimming water maze task and rotorod test, and abnormal eye blink conditioning response. Purkinje cell electrophysiology is abnormal. This mutant mouse strain may be useful in studies of learning, memory and neurophysiology.

Development
A loxP site flanked targeting vector containing neomycin resistance and thymidine kinase genes was utilized in the construction of this mutant. This selection cassette was inserted downstream from the exon encoding the p region and S6 transmembrane (pore-S6) domain, and another loxP site was inserted upstream of the same exon. The construct was electroporated into 129S/SvEv-derived MM13 embryonic stem (ES) cells (obtained from M. Mendelson) which were transiently transfected with a Cre recombinase vector to remove the selection cassette and the exon encoding the p region and S6 transmembrane (pore-S6) domain. Correctly targeted ES cells were injected into C57BL/6 blastocysts. (checking w DI?)

Control Information

  Control
   See control note: B6129SF2/J (Stock 101045) are an approximate control.
   101045 B6129SF2/J (approximate)
 
  Considerations for Choosing Controls

Related Strains

Strains carrying   Hcn1tm2Kndl allele
016566   B6.129S-Hcn1tm2Kndl/J
View Strains carrying   Hcn1tm2Kndl     (1 strain)

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.
Epileptic Encephalopathy, Early Infantile, 24; EIEE24   (HCN1)
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Hcn1tm2Kndl/Hcn1tm2Kndl

        involves: 129S/SvEv * C57BL/6
  • behavior/neurological phenotype
  • *normal* behavior/neurological phenotype
    • basic mnotor functions were all normal basic motor functions were all normal   (MGI Ref ID J:86763)
    • abnormal learning/memory/conditioning   (MGI Ref ID J:86763)
      • abnormal eye blink conditioning behavior
        • a deficiency was observed in latency to peak conditioned response   (MGI Ref ID J:86763)
      • abnormal motor learning
        • there is a learned motor skill deficit in a rotorod test   (MGI Ref ID J:86763)
        • impairment apparently involves learning and memory of relatively fast coordinated movements   (MGI Ref ID J:86763)
      • abnormal spatial learning
        • impaired learning in a water maze test   (MGI Ref ID J:86763)
    • increased thigmotaxis
      • observed during water maze tests   (MGI Ref ID J:86763)
  • cardiovascular system phenotype
  • abnormal myocardial fiber physiology
    • during late polarization, epicardial ventricular myocyte action potentials are shorter than in wild-type cells   (MGI Ref ID J:188823)
    • however, early repolarization is normal   (MGI Ref ID J:188823)
  • nervous system phenotype
  • abnormal action potential
    • during late polarization, epicardial ventricular myocyte action potentials are shorter than in wild-type cells   (MGI Ref ID J:188823)
    • however, early repolarization is normal   (MGI Ref ID J:188823)

Hcn1tm2Kndl/Hcn1tm2Kndl

        involves: 129S/SvEv * C57BL/6J
  • behavior/neurological phenotype
  • abnormal depression-related behavior
    • mice exhibit less time immobile in forced swim and tail suspension tests compared with wild-type mice   (MGI Ref ID J:173355)
View Research Applications

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

Hcn1tm2Kndl related

Neurobiology Research
Behavioral and Learning Defects
Cerebellar Defects
      Purkinje cell defect

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Hcn1tm2Kndl
Allele Name targeted mutation 2, Eric R Kandel
Allele Type Targeted (Null/Knockout)
Common Name(s) HCN1 knockout; Hcn1-;
Mutation Made By Eric Kandel,   Columbia University
Strain of Origin129S/SvEv
ES Cell Line NameMM13
ES Cell Line Strain129S/SvEv
Gene Symbol and Name Hcn1, hyperpolarization-activated, cyclic nucleotide-gated K+ 1
Chromosome 13
Gene Common Name(s) BCNG-1; BCNG1; Bcng1; C630013B14Rik; EIEE24; HAC-2; HAC2; RIKEN cDNA C630013B14 gene; brain cyclic nucleotide gated 1;
Molecular Note A loxP site was inserted upstream of the pore-S6 domain containing exon. At the same time, a floxed neomycin cassette was introduced downstream. Cells in which transient Cre recombinase expression of properly targeted ES cells resulted in excision of both the neomycin gene and the pore-S6 exon were selected. Both mRNA and protein were shown to be absent in the brains of mice homozygous for this allele. [MGI Ref ID J:86763]

Genotyping

Genotyping Information

Genotyping Protocols

Hcn1tm2Kndl,

Separated MCA


Hcn1tm2Kndl, Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Mobley AS; Miller AM; Araneda RC; Maurer LR; Muller F; Greer CA. 2010. Hyperpolarization-activated cyclic nucleotide-gated channels in olfactory sensory neurons regulate axon extension and glomerular formation. J Neurosci 30(49):16498-508. [PubMed: 21147989]  [MGI Ref ID J:166733]

Nolan MF; Malleret G; Lee KH; Gibbs E; Dudman JT; Santoro B; Yin D; Thompson RF; Siegelbaum SA; Kandel ER; Morozov A. 2003. The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells. Cell 115(5):551-64. [PubMed: 14651847]  [MGI Ref ID J:86763]

Additional References

Hcn1tm2Kndl related

Chan CS; Glajch KE; Gertler TS; Guzman JN; Mercer JN; Lewis AS; Goldberg AB; Tkatch T; Shigemoto R; Fleming SM; Chetkovich DM; Osten P; Kita H; Surmeier DJ. 2011. HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease. Nat Neurosci 14(1):85-92. [PubMed: 21076425]  [MGI Ref ID J:170270]

Chen X; Shu S; Bayliss DA. 2009. HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine. J Neurosci 29(3):600-9. [PubMed: 19158287]  [MGI Ref ID J:144849]

Chen X; Shu S; Schwartz LC; Sun C; Kapur J; Bayliss DA. 2010. Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice. J Neurosci 30(7):2611-22. [PubMed: 20164346]  [MGI Ref ID J:157832]

Fenske S; Mader R; Scharr A; Paparizos C; Cao-Ehlker X; Michalakis S; Shaltiel L; Weidinger M; Stieber J; Feil S; Feil R; Hofmann F; Wahl-Schott C; Biel M. 2011. HCN3 contributes to the ventricular action potential waveform in the murine heart. Circ Res 109(9):1015-23. [PubMed: 21903939]  [MGI Ref ID J:188823]

Giocomo LM; Hasselmo ME. 2009. Knock-out of HCN1 subunit flattens dorsal-ventral frequency gradient of medial entorhinal neurons in adult mice. J Neurosci 29(23):7625-30. [PubMed: 19515931]  [MGI Ref ID J:150045]

Giocomo LM; Hussaini SA; Zheng F; Kandel ER; Moser MB; Moser EI. 2011. Grid Cells Use HCN1 Channels for Spatial Scaling. Cell 147(5):1159-70. [PubMed: 22100643]  [MGI Ref ID J:178943]

Horwitz GC; Risner-Janiczek JR; Jones SM; Holt JR. 2011. HCN Channels Expressed in the Inner Ear Are Necessary for Normal Balance Function. J Neurosci 31(46):16814-25. [PubMed: 22090507]  [MGI Ref ID J:177907]

Huang Z; Lujan R; Kadurin I; Uebele VN; Renger JJ; Dolphin AC; Shah MM. 2011. Presynaptic HCN1 channels regulate Cav3.2 activity and neurotransmission at select cortical synapses. Nat Neurosci 14(4):478-86. [PubMed: 21358644]  [MGI Ref ID J:172304]

Huang Z; Walker MC; Shah MM. 2009. Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis. J Neurosci 29(35):10979-88. [PubMed: 19726656]  [MGI Ref ID J:152452]

Knop GC; Seeliger MW; Thiel F; Mataruga A; Kaupp UB; Friedburg C; Tanimoto N; Muller F. 2008. Light responses in the mouse retina are prolonged upon targeted deletion of the HCN1 channel gene. Eur J Neurosci 28(11):2221-30. [PubMed: 19019198]  [MGI Ref ID J:143756]

Leao KE; Leao RN; Walmsley B. 2011. Modulation of dendritic synaptic processing in the lateral superior olive by hyperpolarization-activated currents. Eur J Neurosci 33(8):1462-70. [PubMed: 21366727]  [MGI Ref ID J:176840]

Lewis AS; Vaidya SP; Blaiss CA; Liu Z; Stoub TR; Brager DH; Chen X; Bender RA; Estep CM; Popov AB; Kang CE; Van Veldhoven PP; Bayliss DA; Nicholson DA; Powell CM; Johnston D; Chetkovich DM. 2011. Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J Neurosci 31(20):7424-40. [PubMed: 21593326]  [MGI Ref ID J:173355]

Massella A; Gusciglio M; D'Intino G; Sivilia S; Ferraro L; Calza L; Giardino L. 2009. Gabapentin treatment improves motor coordination in a mice model of progressive ataxia. Brain Res 1301:135-42. [PubMed: 19747469]  [MGI Ref ID J:157412]

Nolan MF; Malleret G; Dudman JT; Buhl DL; Santoro B; Gibbs E; Vronskaya S; Buzsaki G; Siegelbaum SA; Kandel ER; Morozov A. 2004. A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell 119(5):719-32. [PubMed: 15550252]  [MGI Ref ID J:94775]

Orio P; Madrid R; de la Pena E; Parra A; Meseguer V; Bayliss DA; Belmonte C; Viana F. 2009. Characteristics and physiological role of hyperpolarization activated currents in mouse cold thermoreceptors. J Physiol 587(Pt 9):1961-76. [PubMed: 19273581]  [MGI Ref ID J:176542]

Piskorowski R; Santoro B; Siegelbaum SA. 2011. TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron 70(3):495-509. [PubMed: 21555075]  [MGI Ref ID J:174797]

Ramakrishnan NA; Drescher MJ; Khan KM; Hatfield JS; Drescher DG. 2012. HCN1 and HCN2 proteins are expressed in cochlear hair cells: HCN1 can form a ternary complex with protocadherin 15 CD3 and F-actin-binding filamin A or can interact with HCN2. J Biol Chem 287(45):37628-46. [PubMed: 22948144]  [MGI Ref ID J:192134]

Santina LD; Piano I; Cangiano L; Caputo A; Ludwig A; Cervetto L; Gargini C. 2012. Processing of retinal signals in normal and HCN deficient mice. PLoS One 7(1):e29812. [PubMed: 22279546]  [MGI Ref ID J:184238]

Santoro B; Piskorowski RA; Pian P; Hu L; Liu H; Siegelbaum SA. 2009. TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron 62(6):802-13. [PubMed: 19555649]  [MGI Ref ID J:154954]

Tsay D; Dudman JT; Siegelbaum SA. 2007. HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons. Neuron 56(6):1076-89. [PubMed: 18093528]  [MGI Ref ID J:136886]

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 & HusbandryThe resulting chimeric animals were crossed to 129S/SvEv mice, and then backcrossed to C57BL/6 once. Heterozygotes were bred to generate homozygotes.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2525.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Frozen Products

Price (US dollars $)
Frozen Embryo $1650.00

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryopreserved Embryos
    Available to most shipping destinations1
    This strain is also available as cryopreserved embryos2. Orders for cryopreserved embryos may be placed with our Customer Service Department. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos, please visit our Cryopreserved Embryos web page.

    1 Shipments cannot be made to Australia due to Australian government import restrictions.
    2 Embryos for most strains are cryopreserved at the two cell stage while some strains are cryopreserved at the eight cell stage. If this information is important to you, please contact Customer Service.
  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $3283.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Frozen Products

Price (US dollars $)
Frozen Embryo $2145.00

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryopreserved Embryos
    Available to most shipping destinations1
    This strain is also available as cryopreserved embryos2. Orders for cryopreserved embryos may be placed with our Customer Service Department. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos, please visit our Cryopreserved Embryos web page.

    1 Shipments cannot be made to Australia due to Australian government import restrictions.
    2 Embryos for most strains are cryopreserved at the two cell stage while some strains are cryopreserved at the eight cell stage. If this information is important to you, please contact Customer Service.
  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Control Information

  Control
   See control note: B6129SF2/J (Stock 101045) are an approximate control.
   101045 B6129SF2/J (approximate)
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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