Transgenic mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, in Aller et al., 2015. Furthermore, a novel de novo probably damaging missense variant in GRIK4 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).
Molecular Function
This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. The protein encoded by this gene forms functional heteromeric kainate-preferring ionic channels with the subunits encoded by related gene family members.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Increased Dosage of High-Affinity Kainate Receptor Gene grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features.
Overexpression of Grik4 in the forebrain of mice causes social impairment and increase in anxiety as well as changes in synaptic transmission in the hippocampal trisynaptic circuit.
References
Type
Title
Author, Year
Additional
Genetic ablation of the GluK4 kainate receptor subunit causes anxiolytic and antidepressant-like behavior in mice.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Exon 14 of Grik4 gene was targeted with a loxP site targeted upstream of exon14, and a floxed neo cassette was inserted downstream.The founder lines containing the targeted gene were crossed with transgenic mice expressing cre recombinase under the promoter for protamine 1, which leads to recombination and excision of exon 14 from all tissues being activated in the male germ line.
Allele Type: Strain of Origin: Genetic Background: C57BL/6*129SVE
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Exon 14 of Grik4 gene was targeted with flanking loxP sites in mouse ES cells. There founder lines containing the targeted gene were crossed with transgenic mice expressing cre recombinase under the promoter for protamine 1, which leads to recombination and excision of exon 4 from all tissues being activated in the male germ line.
Allele Type: Strain of Origin: Genetic Background: C57BL/6*129SVE
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Grik4 homozygous null mice were crossed with Grik5 homozygous null mice to give rise to the double KO mice.
Allele Type: Strain of Origin: Genetic Background: C57BL/6*129SVE
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The targeting construct had loxP sites flanking exon 16 of Grik4 gene. Mice positive for this construct were crossed with mice homozygous for a transgene encoding Cre recombinase under the EIIa promoter than causes exon 16 excision via recombination in the early embryonic stages.
Allele Type: Targeted(knockout)
Strain of Origin: Genetic Background: C57BL/6*129SVE
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Kainate (0.15 nmol, in PBS) was stereotaxically injected in the hippocampi of the Grik4 KO mice.
Allele Type: Targeted(knockout)
Strain of Origin: Genetic Background: C57BL/6*129SVE
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Transgenic
Mutation:
A myc-tagged Grik4 construct (from rat) was developed under the control of a CamKII promoter. This construct was injected into the pronucleus of fertilized eggs to generate the founder lines. Two of these founder lines with similar expression of Grik4 (over expression because of an additional transgene) were used in all the analyses.
Allele Type: Transgenic
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A targeting construct containing two lox P sites flanking exon 14 of the Grik4 gene was generated and injected into embryonic mouse cells (Fernandes et al., 2009; PMID 19778510).
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Dr. A. Contractor (Northwestern University)
Description: Grik4 null mice have significantly reduced anxiety compared to wild type controls in several tasks including elevated zero maze. the latency to restart feeding is also shorter in the novelty induced suppressed feeding paradigm and the number of marbles buried in a brightly lit novel cage is also lesser than the ones buried by wild type controls. over all authors take the results of these tests to indicate reduction in anxiety
Exp Paradigm: Novelty-suppressed feeding paradigm
Description: Grik4 null mice have significantly reduced anxiety compared to wild type controls in several tasks including elevated zero maze. the latency to restart feeding is also shorter in the novelty induced suppressed feeding paradigm and the number of marbles buried in a brightly lit novel cage is also lesser than the ones buried by wild type controls. over all authors take the results of these tests to indicate reduction in anxiety
Exp Paradigm: Marble-burying test
Description: Grik4 null mice display a decreased tendency for depression as they actually have an increased intake of sucrose compared to wild type littermate controls in the sucrose intake test, as well as decreased imobility and increased activity in the forced swim test
Exp Paradigm: Sucrose preference test
Description: Grik4 null mice have significantly reduced anxiety compared to wild type controls in several tasks including elevated zero maze. the latency to restart feeding is also shorter in the novelty induced suppressed feeding paradigm and the number of marbles buried in a brightly lit novel cage is also lesser than the ones buried by wild type controls. over all authors take the results of these tests to indicate reduction in anxiety
Exp Paradigm: Elevated zero maze test
Description: Grik4 null mice display a decreased tendency for depression as they actually have an increased intake of sucrose compared to wild type littermate controls in the sucrose intake test, as well as decreased imobility and increased activity in the forced swim test
Exp Paradigm: Forced swim test
Description: Grik4 ko mice have increased distance traveled in the open field test, indicating increased hyperactivity in a novel environment
Exp Paradigm: NA
Description: Grik4 ko mice have impaired startle response at 110 db of sound ( authors note no difference with wt at 80, 90 and 100 db)
Exp Paradigm: NA
Description: Grik4 ko mice have reduced spatial reference memory in the probe trial of the mwm as they do not preferentially spend more time in the target quadrant compared to the other three quadrants, unlike wt controls
Exp Paradigm: NA
Description: Grik4 ko mice have reduced spatial learning in the hidden platform phase of mwm determined by increased path length relative to wt controls in the task
Exp Paradigm: NA
Description: Kainate injected grik4 ko mice had reduced cell death in the ca3 region (indicating a protective role by grik4 ko, to excitotoxicity), compared to wt mice injected with kainate
Exp Paradigm: NA
Description: Grik4-overexp mice have reduced locomotor activity, measured as distance traveled in elevated plus maze, the open field and the light-dark explorationt est
Exp Paradigm: Elevated plus maze test
Description: Grik4-overexp mice have reduced locomotor activity, measured as distance traveled in elevated plus maze, the open field and the light-dark explorationt est
Exp Paradigm: Open field test
Description: Grik4-overexp mice have reduced locomotor activity, measured as distance traveled in elevated plus maze, the open field and the light-dark explorationt est
Exp Paradigm: Light-dark exploration test
Spontaneous post synaptic event frequency: excitatory currents2
Decreased
Description: Mutants showed a decrease in the frequency of spontaneous excitatory post synaptic currents in late spiking cells compared to controls.
Exp Paradigm: NA
Description: Grik4-overexp mice have increased field epsp in the ca1 region of the hippocampal trisynaptic circuit, measured in vivo with intracranial electrodes
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory1
Increased
Description: Grik4-overexp mice have increased frequency of ampa receptor mediated mepscs in the ca3 pyramidal neurons, evoked by activation of mossy fibers
Exp Paradigm: NA
Miniature post synaptic current amplitude: excitatory2
Increased
Description: Mutants showed an increase in the amplitude of ampar-mediated epscs compared to controls. mutants also showed an increase in the amplitude of kainater-mediated epscs compared to controls. moreover, mutants showed an increase in the number of neurons in which kainater-mediated erscs could be resolved (13/32 in mutants compared to 10/41 in controls).
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory2
Increased
Description: Mutants showed an increase in the frequency of miniature post synaptic currents in regular spiking cells compared to controls.
Exp Paradigm: Regular spiking cells
Spontaneous post synaptic event amplitude: excitatory currents1
Increased
Description: Grik4-overexp mice have increased amplitude of kainate receptor mediated spontaneous synaptic transmission in the ca3 pyramidal cells
Exp Paradigm: NA
Miniature post synaptic current amplitude: excitatory2
Increased
Description: Mutants showed an increase in the amplitude of miniature post synaptic currents in regular spiking cells compared to controls.
Exp Paradigm: Regular spiking cells
Spontaneous post synaptic event frequency: inhibitory currents2
Increased
Description: Mutants showed an increase in the frequency of spontaneous inhibitory post synaptic currents in late spiking cells compared to controls.
Exp Paradigm: NA
Miniature post synaptic current amplitude: excitatory2
Decreased
Description: Mutants showed a decrease in the amplitude of miniature post synaptic currents in late spiking cells compared to controls.
Exp Paradigm: Late spiking cells
Spontaneous post synaptic event frequency: excitatory currents2
Increased
Description: Mutants showed an increase in the frequency of spontaneous excitatory post synaptic currents in regular spiking cells compared to controls.
Exp Paradigm: NA
Miniature post synaptic current amplitude: excitatory1
Increased
Description: Grik4-overexp mice have increased amplitude of ampa receptor mediated mepscs in the ca3 pyramidal neurons, evoked by activation of mossy fibers
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory2
Decreased
Description: Mutants showed a decrease in the frequency of miniature post synaptic currents in late spiking cells compared to controls.
Exp Paradigm: Late spiking cells
Description: Grik4-overexp mcie show an increased tendency to spend time at the corners of the cage containing the familiar mouse ( like withdrawal or non-engaging), authors note that this is not seen in the wild type controls at all
Exp Paradigm: NA
Description: Grik4-overexp mice show no preference to a novel target mouse over a familiar one and spend the same amount of time with both targets, unlike wild type controls
Exp Paradigm: NA
Description: Grik4-overexp mice show increase in anxiety as they spend lesser time in the center of the open field chamber and the open arms of the elevated plus maze compared to wild type controls and more time in the dark in the light-dark exploration tests
Exp Paradigm: Open field test
Description: Grik4-overexp mice show reduced intake of sucrose indicating increased anhedonia or depression and also have a larger index of immobility in the forced swim test again indicating increase in depression
Exp Paradigm: Sucrose preference test
Description: Grik4-overexp mice show increase in anxiety as they spend lesser time in the center of the open field chamber and the open arms of the elevated plus maze compared to wild type controls and more time in the dark in the light-dark exploration tests
Exp Paradigm: Light-dark exploration test
Description: Grik4-overexp mice show reduced intake of sucrose indicating increased anhedonia or depression and also have a larger index of immobility in the forced swim test again indicating increase in depression
Exp Paradigm: Forced swim test
Description: Grik4-overexp mice show increase in anxiety as they spend lesser time in the center of the open field chamber and the open arms of the elevated plus maze compared to wild type controls and more time in the dark in the light-dark exploration tests
Exp Paradigm: Elevated plus maze test
Miniature post synaptic current frequency: excitatory1
Increased
Description: Mutants showed an increase in the amplitude of miniature post synaptic currents in late spiking cells compared to controls.
Exp Paradigm: Late spiking cells
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Mutants showed a decrease in the amplitude of miniature post synaptic currents in regular spiking cells compared to controls.
Exp Paradigm: Regular spiking cells
