Overview

GluA1 knockout mice exhibit behavioral, social, and cognitive deficits. They may have applications in studies related to behavioral, social and cognitive abnormalities, hippocampal synaptic transmission/plasticity, and nociception, as well as neuropsychiatric disorders such as schizophrenia and depression/mania.

Donating Investigator

Rolf Sprengel, Max Planck Institute for Medical Res

Genetic overview

Genetic Background	Generation

Gria1^tm1Rsp

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Gria1	glutamate receptor, ionotropic, AMPA1 (alpha 1)

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Research Applications

Neurobiology Research
Research Tools
Sensorineural Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The GluA1 knockout allele (also called GluA1^-, GluR-A^-, or A1-lox) has a deletion of the sequences necessary in formation of the glutamate receptor transmembrane domain ion channel pore (exon 11). No GluA1 protein expression is detected from the targeted allele. Homozygous mice are viable and fertile, with behavioral, social, and cognitive deficits. Specifically, homozygotes have profound impairment of several different spatial working memory tasks and selective impairment on short-term recognition memory tasks. Homozygotes show no alterations on spatial reference memory tasks or long-term memory tasks. GluA1^-/- mice also have novelty- and stress-induced hyperactivity, and increased anxiety-related responses. Hippocampal CA1 pyramidal neurons from homozygous mice have strongly reduced extrasynaptic AMPA currents and do not show the dendritic distance-dependent scaling of excitatory synaptic strengths seen in wildtype neurons.

Development

A targeting vector was designed to insert a loxP site upstream of exon 11, and a loxP-flanked neo cassette (from ploxpneo3) downstream of exon 11 of the glutamate receptor, ionotropic, AMPA1 [alpha 1] gene (Gria1; GluR-A, GluA1). This loxP::exon11::loxP::neo::loxP construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl⁺-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells with the GluR-A^neo allele (also called 3loxP allele) were then transiently transfected with a Cre recombinase-expressing plasmid. The resulting ES cells with the GluR-A^- genotype (both exon 11 and neo selection cassette removed; leaving a single loxP site remaining) were injected into recipient blastocysts. Chimeric mice were bred with C57BL/6 mice to establish the mutant colony. The donating investigator reports that GluR-A^- mice were subsequently backcrossed to C57BL/6NCrl mice for ten generations prior to sending to The Jackson Laboratory Repository in 2012. Upon arrival, mice were bred to C57BL/6NJ inbred mice (Stock No. 005304) for at least one generation.

Control Suggestions

005304 C57BL/6NJ

Additional Information

Considerations for Choosing Controls

Selected References

Resnik E; McFarland JM; Sprengel R; Sakmann B; Mehta MR. 2012. The Effects of GluA1 Deletion on the Hippocampal Population Code for Position. J Neurosci 32(26):8952-68PubMed: 22745495 MGI: J:185645
Zamanillo D; Sprengel R; Hvalby O; Jensen V; Burnashev N; Rozov A; Kaiser KM; Koster HJ; Borchardt T; Worley P; Lubke J; Frotscher M; Kelly PH; Sommer B; Andersen P; Seeburg PH; Sakmann B. 1999. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning [see comments] Science 284(5421):1805-11PubMed: 10364547 MGI: J:55695

View All References

Genetics

Gria1^tm1Rsp

Allele Symbol: Gria1^tm1Rsp

Allele Name	targeted mutation 1, Rolf Sprengel
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	GluA1-; GluR1-; GluR-A-; GluRA-
Gene Symbol and Name	Gria1, glutamate receptor, ionotropic, AMPA1 (alpha 1)
Gene Synonym(s)
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	11
General Note	Phenotypic Similarity to Human Syndrome: Schizoaffective Disorder (J:167264).
Molecular Note	A single loxP site was inserted into intron 10 and a loxP flanked neomycin selection cassette was inserted into exon 11. The loxP-flanked sequences were deleted in ES cells by transient Cre expression prior to the production of chimeric mice. The final heritable allele contains a single loxP site replacing exon 11 and flanking intronic sequences. Immunohistochemistry experiments confirmed that no detectable protein is expressed from this allele.

Disease/Phenotype

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

schizoaffective disorder

Research Areas By Phenotype

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

Neurobiology Research
- Neurotransmitter Receptor and Synaptic Vesicle Defects
- Behavioral and Learning Defects
  - high anxiety
- Cortical Defects
- Channel and Transporter Defects
  - calcium: glutamate receptor
- Receptor Defects
  - glutamate receptor: ionotropic
Research Tools
- Neurobiology Research
Sensorineural Research
- Nociception

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Gria1^tm1Rsp/Gria1^tm1Rsp
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

behavior/neurological phenotype

abnormal behavioral response to xenobiotic
- animals display enhanced context-dependent sensitization to D-amphetamine compared to wild-type or Gria1^tm1Erk mice
- fects still produce significant nociception in mutants
- unlike wild-type, mice do not show significant tolerance to the antinociceptive effect of morphine as determined by the thermal tail flick test; repeated doses with increasing doses of morphine that produce tolerance in wild-type to the antinociceptive effects still produce significant nociception in mutants

abnormal locomotor behavior
- duration of locomotor activity is slightly higher than controls in males kept isolated for 1, 5, or 21 days
- increased locomotor activity response to morphine injection is greater than wild-type; however baseline values are higher than controls

abnormal response to new environment
- mice are slightly hyperactive when placed in a novel cage, but do show habituation upon repeated exposure to novel cages
- upon repeated exposure, both mutants and wild-type show habituation but mutants still show slight difference in ambulation

abnormal sexual interaction
- males exhibit less sniffing of body of females than wild-type males

abnormal social investigation
- frequency and duration of partner exploration are increased in male mice isolated for 1, 5, or 21 days compared to controls

decreased aggression towards males
- after 30 days in isolation, male mutants do not show increased consummate aggression towards other animals when placed together, in contrast to wild-type males which show high levels of aggression towards other males
- after pair-housing with a female for 5 days, mutants show no increased aggressive behavior toward an intruder male whereas aggression is higher in wild-type males
- in resident-intruder test, individually tested male mice isolated for 1, 5, or 21 days show reduced frequency and duration of consummate and ambivalent aggression towards an intruder in the resident animal's cage
- mutants show a greater duration of defensive behavior after 30 days of isolation than wild-type males

decreased anxiety-related response
- in elevated plus-maze tests, mutant show shorter latencies to enter closed to first entry of open arms, decreased freezing and more entries into open arms compared to wild-type littermates

decreased behavioral withdrawal response
- mice show a lower number of naloxone-precipitated behavioral withdrawal symptoms with chronic morphine treatment compared to wild-type littermates

hyperactivity
- slightly hyperactive in novel environment

increased exploration in new environment
- male mice kept isolated for 1, 5, or 21 days show increased duration of passive exploration of environment compared to wild-type littermates

increased vertical activity
- rear frequency and duration are increased compared to controls in male mice isolated for 1, 5, or 21 days

growth/size/body region phenotype

decreased body size
- mice are smaller than wild-type littermates during first postnatal weeks, but size normalizes post-weaning

homeostasis/metabolism phenotype

abnormal serotonin level
- ratio of 5-hydroxyindoleacetic acid to serotonin in hippocampus are lower than in wild-type after 4 weeks of social isolation; in general, ratios are lower in mutant brains, but only significant decrease is detected in hippocampus

mammalian phenotype

behavior/neurological phenotype
- Normal - no deficits in spatial learning or spatial memory acquisition are observed in mutants compared to controls

homeostasis/metabolism phenotype
- Normal - after 4 weeks of social isolation, dopamine levels in the brain of males are similar to controls, as are plasma testosterone levels
- Normal - following morphine injection, both mutant and wild-type mice show similar morphine levels in brain tissue and plasma samples, indicating similar pharmacokinetics between the genotypes

nervous system phenotype
- Normal - dendritic and spontaneous calcium transients are similar in mutants and wild-type mice
- Normal - pyramidal cells from hippocampal CA1 region have normal dendrites and spines, and normal morphology of excitatory synapses relative to controls

nervous system phenotype

abnormal serotonin level
- ratio of 5-hydroxyindoleacetic acid to serotonin in hippocampus are lower than in wild-type after 4 weeks of social isolation; in general, ratios are lower in mutant brains, but only significant decrease is detected in hippocampus

reduced AMPA-mediated synaptic currents
- AMPA currents measured in membrane patches from acute brain slices are strongly reduced compared to wild-type

reduced long term potentiation
- in CA1 slices from adult mice, tetanization produces a persistent potentiation of synaptic responses indicated by increased average field EPSP slopes in wild-type, but mutant mice show no LTP (fEPSPs are not different from pretetanic controls
- in presence of bicuculline, LTP is absent in mutants but tetanized wild-type controls show 140% (control pathway: 100%) LTP
- Normal - paired-pulse facilitation at CA1 excitatory synapses is similar between mutants and controls

Genotype: Gria1^tm1Rsp/Gria1^tm1Rsp
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

behavior/neurological phenotype

abnormal emotion/affect behavior
- all these behaviors are indicative of manic-like phenotype
- in repeated exposure to elevated plus-maze, mutants make more open entries than wild-type, regardless of trial, and exhibit more open time; mutants make more closed arm entries on trial 2 but not trial 1
- in the elevated plus-maze, mutants make more open and center entries and have more center time but less closed time, than wild-type mice
- in the light/dark emergence test, mutants make more shelter exits and show more frequent scanning of the shelter than wild-type, although they do not spend more time out of the shelter than wild-type mice, indicating an increase in risk assessment
- lithium treatment partially rescues the elevated maze test phenotype, with mutants making fewer open entries compared to untreated mutants

Genotype: Gria1^tm1Rsp/Gria1^tm1Rsp
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * CBA/J

behavior/neurological phenotype

abnormal emotion/affect behavior
- all these behaviors are indicative of manic-like phenotype
- in the elevated plus-maze, mutants make more open and center entries and have more center time but less closed time, than wild-type mice
- mutants exhibit a decrease in immobility compared to wild-type during the first and sometimes second forced swim trials
- mutants show less immobility and increased swimming, but no difference in climbing, in a modified forced swim test compared to wild-type mice on trial 1 but not trial 2
- mutants, but not wild-type mice, exhibit a significant increase in immobility by the third forced swim trial, as compared to trial 1
- mutants, but not wild-type mice, exhibit an increase in immobility and a decrease in swimming from trial 1 to 2 of the modified forced swim test

hyperactivity
- in a novel open field

increased exploration in new environment
- Normal - however, movement in a home cage-like environment is no different from wild-type
- mutants travel farther than wild-type mice in a novel open field

induced hyperactivity
- injection stress produces a transient increase in activity in mutants compared to a decrease in locomotor activity in wild-type mice
- restraint stress produces a greater increase in locomotor activity in mutants than in wild-type mice

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - corticosterone levels are similar in mutants as in wild-type after a single forced swim trial

The following phenotype relates to a compound genotype created using this strain

Genotype: Gria1^tm1Rsp/Gria1^tm1Rsp
B6.129-Gria1

behavior/neurological phenotype

abnormal nociception after inflammation
- increased spontaneous nocifensive responses to intraplantar capsaicin, however exhibit normal spinal nociceptive tail flick reflex in response to noxious heat and hindpaw withdrawal in response to thermal or mechanical stimuli

decreased chemical nociceptive threshold
- reduction in nociceptive responses in phase II of formalin test and a significantly longer duration of nocifensive behaviors during phase I of formalin test

increased anxiety-related response
- in the elevated zero-maze, mutants make fewer open entries

integument phenotype

abnormal nociception after inflammation
- increased spontaneous nocifensive responses to intraplantar capsaicin, however exhibit normal spinal nociceptive tail flick reflex in response to noxious heat and hindpaw withdrawal in response to thermal or mechanical stimuli

decreased chemical nociceptive threshold
- reduction in nociceptive responses in phase II of formalin test and a significantly longer duration of nocifensive behaviors during phase I of formalin test

nervous system phenotype

abnormal spinal cord morphology
- number of Ca²⁺-permeable AMPA channels is decreased in laminae of the spinal cord

impaired synaptic plasticity
- loss of acute, short-term nociceptive plasticity in the spinal dorsal horn

reduced AMPA-mediated synaptic currents
- AMPA channel-mediated peak currents on second-order spinal neurons are significantly reduced
- the AMPA/NMDA peak current ratio and current integral ratio are significantly reduced in spinal neurons

References

Resnik E; McFarland JM; Sprengel R; Sakmann B; Mehta MR. 2012. The Effects of GluA1 Deletion on the Hippocampal Population Code for Position. J Neurosci 32(26):8952-68PubMed: 22745495 MGI: J:185645
Zamanillo D; Sprengel R; Hvalby O; Jensen V; Burnashev N; Rozov A; Kaiser KM; Koster HJ; Borchardt T; Worley P; Lubke J; Frotscher M; Kelly PH; Sommer B; Andersen P; Seeburg PH; Sakmann B. 1999. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning [see comments] Science 284(5421):1805-11PubMed: 10364547 MGI: J:55695

Additional - Gria1^tm1Rsp related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Gria1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, homozygous mice may be bred together.
- Additional Breeding and Husbandry Support
Citation
When using the B6N.129-Gria1^tm1Rsp/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #019011 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

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

Pricing & Availability

Cryo Recovery

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Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or Wildtype for Gria1<tm1Rsp>

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Frozen Mouse Embryo	B6N.129-Gria1<tm1Rsp>/J	$2595.00
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Frozen Mouse Embryo	B6N.129-Gria1<tm1Rsp>/J	$3373.50

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Gria1tm1Rsp

Allele Symbol: Gria1tm1Rsp

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Gria1tm1Rsp/Gria1tm1Rspinvolves: 129S1/Sv * 129X1/SvJ * C57BL/6

behavior/neurological phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

mammalian phenotype

nervous system phenotype

Genotype: Gria1tm1Rsp/Gria1tm1Rspinvolves: 129S1/Sv * 129X1/SvJ * C57BL/6J

behavior/neurological phenotype

Genotype: Gria1tm1Rsp/Gria1tm1Rspinvolves: 129S1/Sv * 129X1/SvJ * C57BL/6J * CBA/J

behavior/neurological phenotype

mammalian phenotype

Genotype: Gria1tm1Rsp/Gria1tm1RspB6.129-Gria1

behavior/neurological phenotype

integument phenotype

nervous system phenotype

References

Additional - Gria1tm1Rsp related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Gria1^tm1Rsp

Allele Symbol: Gria1^tm1Rsp

Genotype: Gria1^tm1Rsp/Gria1^tm1Rsp
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

Genotype: Gria1^tm1Rsp/Gria1^tm1Rsp
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

Genotype: Gria1^tm1Rsp/Gria1^tm1Rsp
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * CBA/J

Genotype: Gria1^tm1Rsp/Gria1^tm1Rsp
B6.129-Gria1

Additional - Gria1^tm1Rsp related