Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse Generation ?+N1F0 (28-JUL-08)   Donating Investigator Gregg Homanics,   University of Pittsburgh

Description
The gamma-Aminobutyric acid type A receptors mediate the majority of rapid inhibitory synaptic transmission in the CNS. The beta3 subunit is an essential component of these receptors in many brain regions, especially during development, and is implicated in several pathophysiologic processes. The majority of mice homozygous for the Gabrb3^tm1Geh mutation (or beta3-/-) die at birth with ~60% displaying cleft palate and the remaining ~35% die for unidentified reasons. Homozygous females that survive are fertile but do not care for their pups. Survivors have frequent myoclonus and occasional epileptic seizures, are hypersensitive to external stimuli and handling, have a lack of coordination and display altered responses to certain anesthesias. In addition, the observed behavioral deficits (especially regarding social behaviors) indicate that mutant mice may be a useful model of autism spectrum disorders.

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).

Development
This strain was developed in the laboratory of Dr. Gregg Homanics at the University of Pittsburgh. The vector containing Pgk-neo was inserted by homologous recombination and resulted in deletion of the promoter and exons 1 and 2 of the Gabrb3 gene. The 129X1/SvJ x 129S1/Sv-derived R1 ES cell line was used.

Control Information

	Control
	Wild-type from the colony
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Gabrb3

008310

B6;129-Gabrb3tm2.1Geh/J

View Strains carrying other alleles of Gabrb3     (1 strain)

Additional Web Information

JAX^® NOTES, Winter 2008; 512. JAX^® Mice strain sheds new light on autism.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Angelman Syndrome; AS - Models with phenotypic similarity to human disease where etiologies are distinct.2

2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Gabrb3^tm1Geh/Gabrb3^tm1Geh

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

• lethality-prenatal/perinatal
• perinatal lethality (MGI Ref ID J:39801)
  • 30% with normal palates die neonatally
  • 90% die within 1 day of birth
• life span-post-weaning/aging
• premature death (MGI Ref ID J:39801)
  • animals surviving to birth live an average of 18 weeks
• growth/size phenotype
• decreased body size (MGI Ref ID J:39801)
  • 5-10% that survive to adulthood are runted until weaning but achieve normal body weight by adulthood
• behavior/neurological phenotype
• abnormal motor capabilities/coordination/movement (MGI Ref ID J:39801)
• circling (MGI Ref ID J:108890)
  • many have been observed to run continuously in tight circles for extended periods of time
• hyperactivity (MGI Ref ID J:39801)
• impaired coordination (MGI Ref ID J:39801)
  • have difficulty walking on grids and repeatedly fall off platforms and rotarods
• impaired swimming (MGI Ref ID J:39801)
  • have difficulty swimming
• limb grasping (MGI Ref ID J:39801)
• abnormal parental behavior (MGI Ref ID J:39801)
  • failure to nuture offspring
• hyperresponsive (MGI Ref ID J:39801)
  • hyperresponsive to human contact and other sensory stimuli
• seizures (MGI Ref ID J:39801)
  • variable severity of epileptic seizures in mice over 10 weeks of age
• hearing/vestibular/ear phenotype
• abnormal brainstem auditory evoked potential (MGI Ref ID J:112951)
  • at 6 weeks, suprathreshold ABR amplitudes in homozygotes are significantly reduced in amplitude, by at least 50% at all test frequencies and sound levels
• decreased brainstem auditory evoked potential (MGI Ref ID J:112951)
  • at 6 weeks, homozygotes display severe cochlear dysfunction, as shown by highly significant ABR threshold elevations of 20-45 dB across a range of test frequencies, with peak loss occurring at 22.6 kHz
  • ABR threshold elevation corresponds to >2 orders of magnitude of stimulus amplitude
• abnormal cochlea morphology (MGI Ref ID J:112951)
  • at >24 weeks, homozygotes exhibit basal-turn histopathology
  • rarity and fragility of homozygotes prevented evaluation of cochlear histopathology at 6 weeks, as none were killed at this age
• abnormal cochlear IHC afferent innervation (MGI Ref ID J:112951)
  • at >24 weeks, homozygotes display a significant reduction in the density of IHC afferent innervation relative to age-matched wild-type mice, indicating neuropathy
• abnormal cochlear OHC efferent innervation (MGI Ref ID J:112951)
  • at >24 weeks, homozygotes display a reduction in OHC efferent innervation, with fewer efferent axons crossing to OHCs at the level of the tunnel of Corti relative to age-matched wild-type mice
• cochlear inner hair cell degeneration (MGI Ref ID J:112951)
  • at ~24 weeks, homozygotes display a nearly complete loss of IHCs throughout the basal 15% of the cochlear spiral, i.e., from 40 to 90 kHz according to the mouse cochlear frequency map
• cochlear outer hair cell degeneration (MGI Ref ID J:112951)
  • at ~24 weeks, homozygotes display a nearly complete loss of OHCs throughout the basal 15% of the cochlear spiral, i.e., from 40 to 90 kHz according to the mouse cochlear frequency map
• type IV spiral ligament fibrocyte degeneration (MGI Ref ID J:112951)
  • at >24 weeks, homozygotes display widespread loss of type IV fibrocytes, spreading farther apically
• abnormal distortion product otoacoustic emission (MGI Ref ID J:112951)
  • at 6 weeks, homozygotes display significantly elevated DPOAE thresholds across all test frequencies relative to wild-type mice, with DPOAE thresholds of >60 dB at high frequencies
  • at 16 kHz (middle cochlear region), ABR shifts are similar in magnitude to the observed DPOAE shifts, suggesting that the threshold shift arises at, or before, the stage of OHC transduction and amplification
• circling (MGI Ref ID J:108890)
  • many have been observed to run continuously in tight circles for extended periods of time
• sensorineural hearing loss (MGI Ref ID J:112951)
• nervous system phenotype
• abnormal CNS synaptic transmission (MGI Ref ID J:39801)
  • 80% decrease in the maximal amplitude of GABA-activated chloride currents in dorsal root ganglion
• abnormal cochlear IHC afferent innervation (MGI Ref ID J:112951)
  • at >24 weeks, homozygotes display a significant reduction in the density of IHC afferent innervation relative to age-matched wild-type mice, indicating neuropathy
• abnormal cochlear OHC efferent innervation (MGI Ref ID J:112951)
  • at >24 weeks, homozygotes display a reduction in OHC efferent innervation, with fewer efferent axons crossing to OHCs at the level of the tunnel of Corti relative to age-matched wild-type mice
• abnormal cochlear nerve morphology (MGI Ref ID J:112951)
  • at >24 weeks, homozygotes display clear signs of cochlear nerve abnormalities (progressive loss of afferent terminals)
• cochlear ganglion degeneration (MGI Ref ID J:112951)
  • at >24 weeks, homozygotes show partial loss of spiral ganglion cells but only in cochlear regions in which IHCs are degenerated
• cochlear inner hair cell degeneration (MGI Ref ID J:112951)
  • at ~24 weeks, homozygotes display a nearly complete loss of IHCs throughout the basal 15% of the cochlear spiral, i.e., from 40 to 90 kHz according to the mouse cochlear frequency map
• cochlear outer hair cell degeneration (MGI Ref ID J:112951)
  • at ~24 weeks, homozygotes display a nearly complete loss of OHCs throughout the basal 15% of the cochlear spiral, i.e., from 40 to 90 kHz according to the mouse cochlear frequency map
• seizures (MGI Ref ID J:39801)
  • variable severity of epileptic seizures in mice over 10 weeks of age
• small cochlear ganglion (MGI Ref ID J:108890)
  • mutant calretinin-negative cells are smaller at each sampled location in the spiral ganglion relative to wild-type cells
  • the reduction in mean somatic area of mutant calretinin-negative cells is 5.2% in the basal turn, 8.7% in the middle turn, and 12.2% in the apical turn of the spiral ganglion relative to wild-type cells
  • adult homozygotes display significantly smaller cochlear ganglion cell areas at every sampled region in the spiral ganglion, except the apical cochlear turn
  • in contrast, mutant calretinin-positive ganglion cells are of normal size and proportion relative to wild-type cells
• cochlear ganglion hypoplasia (MGI Ref ID J:108890)
  • adult homozygotes show hypoplasia of spiral ganglion cells in the middle and basal turns of the cochlea, while the apical turn remains unaffected
  • spiral ganglion cell hypoplasia is strictly due to a size reduction of calretinin-negative ganglion cells
• small vestibular ganglion (MGI Ref ID J:108890)
  • adult homozygotes display significantly smaller ganglion cell areas in both divisions of Scarpa's ganglion (superior and inferior) relative to wild-type mice
  • mutant calretinin-negative cells are smaller in both divisions of Scarpa's ganglion relative to wild-type cells
  • the reduction in mean somatic area of mutant calretinin-negative cells is 9.5% in the inferior division and 21.5% in the superior division of Scarpa's ganglion
  • in contrast, mutant calretinin-positive ganglion cells are of normal size and proportion relative to wild-type cells
• vestibular ganglion hypoplasia (MGI Ref ID J:108890)
  • adult homozygotes show ganglion cell hypoplasia in both divisions of Scarpa's ganglion
  • Scarpa ganglion cell hypoplasia is strictly due to a size reduction of calretinin-negative ganglion cells
• craniofacial phenotype
• cleft palate (MGI Ref ID J:39801)
  • about 57% exhibit cleft palate
• digestive/alimentary phenotype
• cleft palate (MGI Ref ID J:39801)
  • about 57% exhibit cleft palate

View Research Applications

Research Applications

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

Neurobiology Research
Epilepsy
Neurodevelopmental Defects (Autism)
Receptor Defects (GABA receptor)

Gabrb3^tm1Geh related

Cell Biology Research
Channel and Transporter Defects (chloride: GABAA receptor)

Developmental Biology Research
Neurodevelopmental Defects

Neurobiology Research
Behavioral and Learning Defects
Channel and Transporter Defects (chloride: GABAA receptor)
Epilepsy
Neurodevelopmental Defects
Neurotransmitter Receptor and Synaptic Vesicle Defects
Receptor Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Gabrb3tm1Geh
Allele Name		targeted mutation 1, Gregg E Homanics
Allele Type		Targeted (knock-out)
Common Name(s)		beta3-;
Mutation Made By		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		Gabrb3, gamma-aminobutyric acid (GABA-A) receptor, subunit beta 3
Chromosome		7
Gene Common Name(s)		A230092K12Rik; AW049585; Cp1; ECA5; Gabrb-3; MGC9051; RIKEN cDNA A230092K12 gene; beta3; cleft palate 1; expressed sequence AW049585;
Molecular Note		A neomycin resistance cassette replaced 2.8 kb of sequence, including exons 1-3. [MGI Ref ID J:39801]

Genotyping

Genotyping Information

Genotyping Protocols

Gabrb3^tm1Geh, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Delorey TM; Sahbaie P; Hashemi E; Homanics GE; Clark JD. 2008. Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: A potential model of autism spectrum disorder. Behav Brain Res 187(2):207-20. [PubMed: 17983671]  [MGI Ref ID J:130259]

Homanics GE; DeLorey TM; Firestone LL; Quinlan JJ; Handforth A ; Harrison NL ; Krasowski MD ; Rick CE ; Korpi ER ; Makela R ; Brilliant MH ; Hagiwara N ; Ferguson C ; Snyder K ; Olsen RW. 1997. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci U S A 94(8):4143-8. [PubMed: 9108119]  [MGI Ref ID J:39801]

Additional References

Dellovade TL; Davis AM; Ferguson C; Sieghart W; Homanics GE; Tobet SA. 2001. GABA influences the development of the ventromedial nucleus of the hypothalamus. J Neurobiol 49(4):264-76. [PubMed: 11745664]  [MGI Ref ID J:79217]

Gabrb3^tm1Geh related

DeLorey TM; Handforth A; Anagnostaras SG; Homanics GE; Minassian BA ; Asatourian A ; Fanselow MS ; Delgado-Escueta A ; Ellison GD ; Olsen RW. 1998. Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 18(20):8505-14. [PubMed: 9763493]  [MGI Ref ID J:50564]

Hagiwara N; Katarova Z; Siracusa LD; Brilliant MH. 2003. Nonneuronal expression of the GABA(A) beta3 subunit gene is required for normal palate development in mice. Dev Biol 254(1):93-101. [PubMed: 12606284]  [MGI Ref ID J:83131]

Hashemi E; Sahbaie P; Davies MF; Clark JD; DeLorey TM. 2007. Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of locus coeruleus dendrites. Brain Res 1129(1):191-9. [PubMed: 17156762]  [MGI Ref ID J:117697]

Huntsman MM; Porcello DM; Homanics GE; DeLorey TM; Huguenard JR. 1999. Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 283(5401):541-3. [PubMed: 9915702]  [MGI Ref ID J:124675]

Koo JW; Homanics GE; Balaban CD. 2002. Hypoplasia of spiral and Scarpa's ganglion cells in GABA(A) receptor beta(3) subunit knockout mice. Hear Res 167(1-2):71-80. [PubMed: 12117532]  [MGI Ref ID J:108890]

Krasowski MD; Rick CE; Harrison NL; Firestone LL; Homanics GE. 1998. A deficit of functional GABA(A) receptors in neurons of beta 3 subunit knockout mice. Neurosci Lett 240(2):81-4. [PubMed: 9486477]  [MGI Ref ID J:107951]

Liljelund P; Handforth A; Homanics GE; Olsen RW. 2005. GABA(A) receptor beta3 subunit gene-deficient heterozygous mice show parent-of-origin and gender-related differences in beta3 subunit levels, EEG, and behavior. Brain Res Dev Brain Res 157(2):150-61. [PubMed: 15878204]  [MGI Ref ID J:99362]

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]

Nusser Z; Kay LM; Laurent G; Homanics GE; Mody I. 2001. Disruption of GABA(A) receptors on GABAergic interneurons leads to increased oscillatory power in the olfactory bulb network. J Neurophysiol 86(6):2823-33. [PubMed: 11731539]  [MGI Ref ID J:104000]

Quinlan JJ; Homanics GE; Firestone LL. 1998. Anesthesia sensitivity in mice that lack the beta3 subunit of the gamma-aminobutyric acid type A receptor. Anesthesiology 88(3):775-80. [PubMed: 9523823]  [MGI Ref ID J:46728]

Ramadan E; Fu Z; Losi G; Homanics GE; Neale JH; Vicini S. 2003. GABA(A) receptor beta3 subunit deletion decreases alpha2/3 subunits and IPSC duration. J Neurophysiol 89(1):128-34. [PubMed: 12522165]  [MGI Ref ID J:102972]

Resnick A; Homanics GE; Jung BJ; Peris J. 1999. Increased acute cocaine sensitivity and decreased cocaine sensitization in GABA(A) receptor beta3 subunit knockout mice. J Neurochem 73(4):1539-48. [PubMed: 10501199]  [MGI Ref ID J:57686]

Sinkkonen ST; Homanics GE; Korpi ER. 2003. Mouse models of Angelman syndrome, a neurodevelopmental disorder, display different brain regional GABA(A) receptor alterations. Neurosci Lett 340(3):205-8. [PubMed: 12672542]  [MGI Ref ID J:108025]

Ugarte SD; Homanics GE; Firestone LL; Hammond DL. 2000. Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the beta3 subunit of the GABA(A) receptor Neuroscience 95(3):795-806. [PubMed: 10670447]  [MGI Ref ID J:60491]

Ugarte SD; Homanics GE; Hammond DL. 2001. Effect of embryonic knock-down of GABA(A) receptors on the levels of monoamines and their metabolites in the CNS of the mouse. Brain Res 904(2):290-7. [PubMed: 11406127]  [MGI Ref ID J:70367]

Wisor JP; DeLorey TM; Homanics GE; Edgar DM. 2002. Sleep states and sleep electroencephalographic spectral power in mice lacking the beta(3) subunit of the GABA(A) receptor. Brain Res 955(1-2):221-8. [PubMed: 12419540]  [MGI Ref ID J:80484]

Wong SM; Cheng G; Homanics GE; Kendig JJ. 2001. Enflurane actions on spinal cords from mice that lack the beta3 subunit of the GABA(A) receptor. Anesthesiology 95(1):154-64. [PubMed: 11465553]  [MGI Ref ID J:106235]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Mating System	+/+ sibling x Heterozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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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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