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 Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation N10pN1p (26-FEB-06) Generation Definitions   Donating Investigator Dr. Gregg Homanics,   University of Pittsburgh

Appearance
black
Related Genotype: a/a

Description
Mice that are homozygous null for Gabrd are viable and fertile. Northern blot analysis of -/- adult cerebellar RNA suggests that a chimeric Gabrd/neo transcript is generated from the targeted allele. Western blot analysis fails to detect a Gabrd protein product. Maximal binding for the agonist muscimol was markedly decreased in whole brain homogenates. Consistent with this, in situ autoradiographic analysis indicates a drastic reduction in muscimol binding in most parts of the brain. In general, these mice exhibit a decreased sensitivity to the sedative/hypnotic, anxiolytic and pro-absence effects of neuroactive steroids as determined by sleep time assays, elevated plus-maze assays (measures anxiolytic effect) and the inability of neuroactive steroids to prolong pentylenetetrazol-induced seizures. This decreased sensitivity appears to be selective however, as differential responses to various neuroactive steroids are observed.

Of note, several strains bearing gamma-aminobutyric acid (GABA-A) receptor mutations are available from this donating investigator (Dr. Gregg Homanics, University of Pittsburgh), including Gabra1 (Stock No. 004318), Gabra4 (Stock No. 006874), Gabra6 (Stock No. 002710), Gabrb3 (Stock No. 002711), Gabrd (Stock No. 003725), and Gabrg2 (Stock No. 003137).

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

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Epilepsy, Idiopathic Generalized, Susceptibility to, 10; EIG10   (GABRD)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Gabrd^tm1Geh/Gabrd^tm1Geh

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

• mortality/aging
• postnatal lethality
  • only 20.5% of pups weaned are homozygous for the mutation, indicating that ~5% of homozygotes die prior to weaning   (MGI Ref ID J:64288)
• behavior/neurological phenotype
• abnormal contextual conditioning behavior
  • percent freezing of female Gabrd-deficient mice is significantly greater than that of wild-type during the tone test in a context conditioning paradigm 24 hours after the cued conditioning   (MGI Ref ID J:110073)
• abnormal cued conditioning behavior
  • percent freezing of female Gabrd-deficient mice is significantly greater than that of wild-type during trace conditioning   (MGI Ref ID J:110073)
• absence seizures
  • ganaxolone failed to prolong PTZ-induced absence-like seizures in null mice but increased freezing 74% in controls   (MGI Ref ID J:64288)
• decreased anxiety-related response
  • mutants display fewer open arm entries in the elevated plus maze; injection of ganaxolone to wild-type mice resulted in a 2-fold increase in open arm entries but had no effect on mutants   (MGI Ref ID J:64288)
• impaired behavioral response to anesthetic
  • Gabrd-deficient mice show a 54% and 38% reduction in sleep time duration to alphaxalone at 8 mg/kg and 16 mg/kg respectively compared to controls   (MGI Ref ID J:64288)
  • an injection of 8 mg/kg of pregnanolone results in a 42% reduction in sleep time in mutants compared to controls   (MGI Ref ID J:64288)
• nervous system phenotype
• abnormal inhibitory postsynaptic currents
  • decay time of mini IPSCs is faster in mutants than in wild-type controls   (MGI Ref ID J:64288)
• absence seizures
  • ganaxolone failed to prolong PTZ-induced absence-like seizures in null mice but increased freezing 74% in controls   (MGI Ref ID J:64288)
• reproductive system phenotype
• decreased litter size
  • in the F3 generation, homozygous matings produced statistically fewer pups (6.3 pups/litter) than wild-type pairs (7.6 pups/litter)   (MGI Ref ID J:64288)

Gabrd^tm1Geh/Gabrd^tm1Geh

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

• behavior/neurological phenotype
• abnormal depression-related behavior
  • 18 day postpartum mice exhibit decreased preference for sucrose (anhedonia) compared to virgin mice or postpartum wild-type mice   (MGI Ref ID J:145475)
• • behavioral despair
    • 18 day postpartum mice exhibit decreased latency to immobility and increased immobility time in a forced swim test compared to virgin mice and postpartum wild-type mice   (MGI Ref ID J:145475)
• abnormal maternal nurturing
  • more pups, regardless of genotype, die of maternal neglect or pup cannibalism than in litters nurtured by wild-type mice   (MGI Ref ID J:145475)
  • however, treatment with THIP (a GABA A receptor delta subunit agonist) improves pup survival   (MGI Ref ID J:145475)
• • abnormal pup retrieval
    • postpartum female mice allow pups to disperse more than postpartum wild-type mice   (MGI Ref ID J:145475)
  • pup cannibalization   (MGI Ref ID J:145475)
• abnormal nest building behavior
  • postpartum mice fail to build a proper nest unlike postpartum wild-type mice   (MGI Ref ID J:145475)
• increased anxiety-related response
  • in a resident-intruder assay, postpartum mice exhibit increased digging, burrowing, and circling compared to virgin mice or postpartum wild-type mice without an increase in aggressive behavior   (MGI Ref ID J:145475)
• nervous system phenotype
• abnormal nervous system electrophysiology
  • virgin and 18 day postpartum mice exhibit decreased tonic inhibition in dentate gyrus granule cells compared to virgin and postpartum wild-type mice   (MGI Ref ID J:145475)
  • however, mean conductance of synaptic GABA receptors is normal   (MGI Ref ID J:145475)
• hearing/vestibular/ear phenotype
• *normal* hearing/vestibular/ear phenotype
  • at 6 weeks of age, homozygotes show no signs of cochlear pathology, with normal hearing sensitivity, as determined by ABR/DPOAE assays across various test frequencies, and normal OHC efferent function, as assessed by measuring DPOAE suppression caused by efferent-bundle shocks   (MGI Ref ID J:112951)

View Research Applications

Research Applications

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

Neurobiology Research
Receptor Defects
      GABA receptor

Gabrd^tm1Geh related

Neurobiology Research
Neurotransmitter Receptor and Synaptic Vesicle Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Gabrdtm1Geh
Allele Name		targeted mutation 1, Gregg E Homanics
Allele Type		Targeted (knock-out)
Common Name(s)		delta-; delta0;
Mutation Made By		Dr. Gregg Homanics,   University of Pittsburgh
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		Gabrd, gamma-aminobutyric acid (GABA) A receptor, subunit delta
Chromosome		4
Gene Common Name(s)		AI853201; EIG10; EJM7; GABAA-RD; GEFSP5; expressed sequence AI853201;
General Note		Phenotypic Similarity to Human Syndrome: Postpartum depression (J:145475)
Molecular Note		Insertion of a MC1-neomycin resistance cassette into exon 4 disrupted the gene. Northern blot analysis of cerebellar total RNA from homozygous mutant adult mice detected moderate levels of a novel 2.3kb transcript but not the 1.9kb wild-type transcript. Western blot analysis of cerebellar membranes did not detect the wild-type protein in homozygous mutant mice. [MGI Ref ID J:64288]

Genotyping

Genotyping Information

Genotyping Protocols

Gabrd^tm1Geh, Standard PCR
NEOTD (Generic Neo), Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Mihalek RM; Banerjee PK; Korpi ER; Quinlan JJ; Firestone LL; Mi ZP; Lagenaur C; Tretter V; Sieghart W; Anagnostaras SG; Sage JR; Fanselow MS; Guidotti A; Spigelman I; Li Z; DeLorey TM; Olsen RW; Homanics GE. 1999. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci U S A 96(22):12905-10. [PubMed: 10536021]  [MGI Ref ID J:64288]

Additional References

Peng Z; Hauer B; Mihalek RM; Homanics GE; Sieghart W; Olsen RW; Houser CR. 2002. GABA(A) receptor changes in delta subunit-deficient mice: Altered expression of alpha4 and gamma2 subunits in the forebrain. J Comp Neurol 446(2):179-97. [PubMed: 11932935]  [MGI Ref ID J:75642]

Tretter V; Hauer B; Nusser Z; Mihalek RM; Hoger H; Homanics GE; Somogyi P; Sieghart W. 2001. Targeted disruption of the GABA(A) receptor delta subunit gene leads to an up-regulation of gamma 2 subunit-containing receptors in cerebellar granule cells. J Biol Chem 276(13):10532-8. [PubMed: 11136737]  [MGI Ref ID J:69674]

Wei W; Zhang N; Peng Z; Houser CR; Mody I. 2003. Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci 23(33):10650-61. [PubMed: 14627650]  [MGI Ref ID J:88206]

Gabrd^tm1Geh related

Absalom N; Eghorn LF; Villumsen IS; Karim N; Bay T; Olsen JV; Knudsen GM; Brauner-Osborne H; Frolund B; Clausen RP; Chebib M; Wellendorph P. 2012. alpha4betadelta GABA(A) receptors are high-affinity targets for gamma-hydroxybutyric acid (GHB). Proc Natl Acad Sci U S A 109(33):13404-9. [PubMed: 22753476]  [MGI Ref ID J:188413]

Bright DP; Renzi M; Bartram J; McGee TP; MacKenzie G; Hosie AM; Farrant M; Brickley SG. 2011. Profound desensitization by ambient GABA limits activation of delta-containing GABAA receptors during spillover. J Neurosci 31(2):753-63. [PubMed: 21228184]  [MGI Ref ID J:168225]

Clarkson AN; Huang BS; Macisaac SE; Mody I; Carmichael ST. 2010. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468(7321):305-9. [PubMed: 21048709]  [MGI Ref ID J:166695]

Cope DW; Di Giovanni G; Fyson SJ; Orban G; Errington AC; Lorincz ML; Gould TM; Carter DA; Crunelli V. 2009. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med 15(12):1392-8. [PubMed: 19966779]  [MGI Ref ID J:155872]

Duveau V; Laustela S; Barth L; Gianolini F; Vogt KE; Keist R; Chandra D; Homanics GE; Rudolph U; Fritschy JM. 2011. Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis. Eur J Neurosci 34(3):362-73. [PubMed: 21722213]  [MGI Ref ID J:177937]

Glykys J; Mann EO; Mody I. 2008. Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus? J Neurosci 28(6):1421-6. [PubMed: 18256262]  [MGI Ref ID J:131956]

Glykys J; Mody I. 2007. The main source of ambient GABA responsible for tonic inhibition in the mouse hippocampus. J Physiol 582(Pt 3):1163-78. [PubMed: 17525114]  [MGI Ref ID J:140832]

Glykys J; Peng Z; Chandra D; Homanics GE; Houser CR; Mody I. 2007. A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol. Nat Neurosci 10(1):40-8. [PubMed: 17159992]  [MGI Ref ID J:117464]

Herd MB; Foister N; Chandra D; Peden DR; Homanics GE; Brown VJ; Balfour DJ; Lambert JJ; Belelli D. 2009. Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors. Eur J Neurosci 29(6):1177-87. [PubMed: 19302153]  [MGI Ref ID J:147113]

Herd MB; Haythornthwaite AR; Rosahl TW; Wafford KA; Homanics GE; Lambert JJ; Belelli D. 2008. The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells. J Physiol 586(4):989-1004. [PubMed: 18079158]  [MGI Ref ID J:176405]

Jimenez-Gonzalez C; Pirttimaki T; Cope DW; Parri HR. 2011. Non-neuronal, slow GABA signalling in the ventrobasal thalamus targets delta-subunit-containing GABA(A) receptors. Eur J Neurosci 33(8):1471-82. [PubMed: 21395866]  [MGI Ref ID J:176379]

Korpi ER; Mihalek RM; Sinkkonen ST; Hauer B; Hevers W; Homanics GE; Sieghart W; Luddens H. 2002. Altered receptor subtypes in the forebrain of GABA(A) receptor delta subunit-deficient mice: recruitment of gamma 2 subunits. Neuroscience 109(4):733-43. [PubMed: 11927155]  [MGI Ref ID J:126645]

Liang J; Zhang N; Cagetti E; Houser CR; Olsen RW; Spigelman I. 2006. Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors. J Neurosci 26(6):1749-58. [PubMed: 16467523]  [MGI Ref ID J:105649]

Maguire J; Ferando I; Simonsen C; Mody I. 2009. Excitability changes related to GABAA receptor plasticity during pregnancy. J Neurosci 29(30):9592-601. [PubMed: 19641122]  [MGI Ref ID J:151322]

Maguire J; Mody I. 2008. GABA(A)R plasticity during pregnancy: relevance to postpartum depression. Neuron 59(2):207-13. [PubMed: 18667149]  [MGI Ref ID J:145475]

Maguire JL; Stell BM; Rafizadeh M; Mody I. 2005. Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 8(6):797-804. [PubMed: 15895085]  [MGI Ref ID J:99230]

Maison SF; Rosahl TW; Homanics GE; Liberman MC. 2006. Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABA(A) receptor subunits alpha1, alpha2, alpha5, alpha6, beta2, beta3, or delta. J Neurosci 26(40):10315-26. [PubMed: 17021187]  [MGI Ref ID J:112951]

Mann EO; Mody I. 2010. Control of hippocampal gamma oscillation frequency by tonic inhibition and excitation of interneurons. Nat Neurosci 13(2):205-12. [PubMed: 20023655]  [MGI Ref ID J:156705]

Mihalek RM; Bowers BJ; Wehner JM; Kralic JE; VanDoren MJ; Morrow AL; Homanics GE. 2001. GABA(A)-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin Exp Res 25(12):1708-18. [PubMed: 11781502]  [MGI Ref ID J:113055]

Peng Z; Hauer B; Mihalek RM; Homanics GE; Sieghart W; Olsen RW; Houser CR. 2002. GABA(A) receptor changes in delta subunit-deficient mice: Altered expression of alpha4 and gamma2 subunits in the forebrain. J Comp Neurol 446(2):179-97. [PubMed: 11932935]  [MGI Ref ID J:75642]

Porcello DM; Huntsman MM; Mihalek RM; Homanics GE; Huguenard JR. 2003. Intact synaptic GABAergic inhibition and altered neurosteroid modulation of thalamic relay neurons in mice lacking delta subunit. J Neurophysiol 89(3):1378-86. [PubMed: 12626617]  [MGI Ref ID J:103034]

Santhakumar V; Jones RT; Mody I. 2010. Developmental regulation and neuroprotective effects of striatal tonic GABAA currents. Neuroscience 167(3):644-55. [PubMed: 20206233]  [MGI Ref ID J:161493]

Shen H; Gong QH; Aoki C; Yuan M; Ruderman Y; Dattilo M; Williams K; Smith SS. 2007. Reversal of neurosteroid effects at alpha4beta2delta GABAA receptors triggers anxiety at puberty. Nat Neurosci 10(4):469-77. [PubMed: 17351635]  [MGI Ref ID J:121282]

Shen H; Sabaliauskas N; Sherpa A; Fenton AA; Stelzer A; Aoki C; Smith SS. 2010. A critical role for alpha4betadelta GABAA receptors in shaping learning deficits at puberty in mice. Science 327(5972):1515-8. [PubMed: 20299596]  [MGI Ref ID J:158728]

Spigelman I; Li Z; Banerjee PK; Mihalek RM; Homanics GE; Olsen RW. 2002. Behavior and physiology of mice lacking the GABAA-receptor delta subunit. Epilepsia 43 Suppl 5:3-8. [PubMed: 12121286]  [MGI Ref ID J:103021]

Stell BM; Brickley SG; Tang CY; Farrant M; Mody I. 2003. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci U S A 100(24):14439-44. [PubMed: 14623958]  [MGI Ref ID J:125426]

Tretter V; Hauer B; Nusser Z; Mihalek RM; Hoger H; Homanics GE; Somogyi P; Sieghart W. 2001. Targeted disruption of the GABA(A) receptor delta subunit gene leads to an up-regulation of gamma 2 subunit-containing receptors in cerebellar granule cells. J Biol Chem 276(13):10532-8. [PubMed: 11136737]  [MGI Ref ID J:69674]

Vicini S; Losi G; Homanics GE. 2002. GABA(A) receptor delta subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons. Neuropharmacology 43(4):646-50. [PubMed: 12367609]  [MGI Ref ID J:97337]

Wei W; Zhang N; Peng Z; Houser CR; Mody I. 2003. Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci 23(33):10650-61. [PubMed: 14627650]  [MGI Ref ID J:88206]

Wiltgen BJ; Sanders MJ; Ferguson C; Homanics GE; Fanselow MS. 2005. Trace fear conditioning is enhanced in mice lacking the delta subunit of the GABAA receptor. Learn Mem 12(3):327-33. [PubMed: 15897254]  [MGI Ref ID J:110073]

Winsky-Sommerer R; Vyazovskiy VV; Homanics GE; Tobler I. 2007. The EEG effects of THIP (Gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors. Eur J Neurosci 25(6):1893-9. [PubMed: 17408425]  [MGI Ref ID J:122898]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

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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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.

See Terms of Use tab for General Terms and Conditions

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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