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Cited by 173Bipolar Disorder and TreatmentNeuroscience and Neuropharmacology ResearchTreatment of Major Depression

Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania

Open access
Shaltiel, G, Maeng, S, Malkesman, O, Pearson, B, Schloesser, R J, Tragon, T, Rogawski, M, Gasior, M +3 more·2008·Molecular Psychiatry
DOI 10.1038/mp.2008.20PMC PMC2804880
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Abstract

The glutamate receptor 6 (GluR6 or GRIK2, one of the kainate receptors) gene resides in a genetic linkage region (6q21) associated with bipolar disorder (BPD), but its function in affective regulation is unknown. Compared with wild-type (WT) and GluR5 knockout (KO) mice, GluR6 KO mice were more active in multiple tests and super responsive to amphetamine. In a battery of specific tests, GluR6 KO mice also exhibited less anxious or more risk-taking type behavior and less despair-type manifestations, and they also had more aggressive displays. Chronic treatment with lithium, a classic antimanic mood stabilizer, reduced hyperactivity, aggressive displays and some risk-taking type behavior in GluR6 KO mice. Hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. The membrane levels of other glutamatergic receptors were not significantly altered by GluR6 ablation or chronic lithium treatment. Together, these biochemical and behavioral results suggest a unique role for GluR6 in controlling abnormalities related to the behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggressiveness, driven or increased goal-directed pursuits, risk taking and supersensitivity to psychostimulants. Whether GluR6 perturbation is involved in the mood elevation or thought disturbance of mania and the cyclicity of BPD are unknown. The molecular mechanism underlying the behavioral effects of lithium in GluR6 KO mice remains to be elucidated.

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Crossref · 10.1038/mp.2008.20

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  • GluR6 knock-out mice are more aggressive than wild type mice.

    “These mice are also more aggressive than wild type mice.”

    From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Shaltiel et al., 2008

  • Lithium treatment reduced GluR6 knock-out mice hyperactivity, increased anxiety, and reduced aggressive behavior.

    “Lithium treatment was able to reduce their hyperactivity, increase anxiety, and reduce their aggressive behavior.”

    From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Shaltiel et al., 2008

  • Glutamate receptor 6 (GluR6) knock-out mice are hyperactive, have an increased response to amphetamine, have low anxiety-related behaviors, and have lower depression-like behavior.

    “Indeed, Glutamate receptor 6 (GluR6) knock-out mice are hyperactive, have an increased response to amphetamine, have low anxiety-related behaviors, and have lower depression-like behavior (Shaltiel et al., 2008).”

    From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Shaltiel et al., 2008

  • Lithium further reduced immobility in the forced swim test in GluR6 knock-out mice instead of bringing the mice back towards wild type levels as seen with the Clock mutants.

    “However, interestingly, lithium further reduced their immobility in the forced swim test (a measure of depression-like behavior) instead of bringing the mice back towards wild type levels as seen with the Clock mutants.”

    From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Shaltiel et al., 2008

  • Lithium treatment had no effect on levels of GluR5 in the hippocampus of the GluR6 knock-out animals.

    “Lithium treatment had no effect on levels of GluR5 in the hippocampus of the GluR6 knock-out animals suggesting that this is not the mechanism by which lithium is restoring normal activity and anxiety-related behavior to these mice (Shaltiel et al., 2008).”

    From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Shaltiel et al., 2008

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Authors
Shaltiel, G., Maeng, S., Malkesman, O., Pearson, B., Schloesser, R. J., Tragon, T., Rogawski, M., Gasior, M., Luckenbaugh, D., Chen, G., & Manji, H. K.
Affiliations
National Institutes of Health (US)
Corresponding author
Manji, H K
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2008-03-11
Volume
13
Issue
9
Pages
858-872
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2008.20
PMC
PMC2804880
OpenAlex
W2169105392
Cited by
173
References
64
Citations by year
2026: 4 · 2025: 6 · 2024: 7 · 2023: 1 · 2022: 8 · 2021: 10 · 2020: 5 · 2019: 12 · 2018: 4 · 2017: 5 · 2016: 10 · 2015: 16 · 2014: 10 · 2013: 12 · 2012: 6
FWCI
13.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (ZIAMH002872)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
GluR6, kainate receptors, bipolar disorder, mania, GluR5, lithium, hyperactivity, aggression, risk-taking, despair, anxiety, hippocampus, prefrontal cortex, glutamate receptors, knockout mice
MeSH terms
GluK2 Kainate Receptor, Analysis of Variance, Animals, Avoidance Learning, Behavioral Symptoms, Bipolar Disorder, Exploratory Behavior, Interpersonal Relations, Mice, Inbred C57BL, Risk-Taking, Swimming, Time Factors, Lithium Carbonate, Receptors, Kainic Acid, Kainic Acid Receptors, Mice, Knockout, Antimanic Agents, Maze Learning, Mice

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