Shaltiel G, Maeng S, Malkesman O, Pearson B, Schloesser RJ, Tragon T et al. Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania. Mol Psychiatry 13: 858-872

Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Molecular Psychiatry (Impact Factor: 14.5). 04/2008; 13(9):858-72. DOI: 10.1038/mp.2008.20
Source: PubMed


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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    • "There is substantial evidence suggesting that GluK2 plays a role in mood disorders . Major depressive disorder has been found to correlate with decreased GluK2 expression in the entorhinal cortex (Beneyto et al. 2007), although mice with genetically deleted GluK2 receptor exhibit less anxious or more risk-taking behaviour and less manifestation of despair (Shaltiel et al. 2008). 5-HT 2C receptor is implicated in the pathophysiology of major depression (Iwamoto et al. 2009). "
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    ABSTRACT: Previously, we reported that chronic treatment with fluoxetine increased gene expression of 5-hydroxytryptamine receptor 2B (5-HT2BR), cytosolic phospholipase 2α (cPLA2α), glutamate receptor, ionotropic kainate 2 (GluK2) and adenosine deaminase acting on RNA 2 (ADAR2), in cultured astrocytes and astrocytes freshly isolated from transgenic mice tagged with an astrocyte-specific marker. In contrast, neurones isolated from transgenic mice tagged with a neurone-specific marker and exposed to fluoxetine showed an increase in gene expression of glutamate receptor, ionotropic kainate 4 (GluK4) and 5-hydroxytryptamine receptor 2C (5-HT2CR). In a mouse model of anhedonia, the downregulation of 5-HT2BR, cPLA2α, ADAR2 and GluK4 but not GluK2 and 5-HT2CR was detected. To investigate the effects of chronic mild stress (CMS) and/or fluoxetine treatment on gene expression of 5-HT2BR, 5-HT2CR, cPLA2α, ADAR2, GluK2 and GluK4 specifically in astrocytes and neurones. Transgenic mice tagged with either astrocyte- or neurone-specific markers were exposed to the CMS. Real-time PCR was applied to determine expression of messenger RNA (mRNA). We found that (i) mRNAs of the 5-HT2BR and cPLA2α in astrocytes and GluK4 in neurones were significantly reduced in mice that became anhedonic; the mRNA levels were restored by fluoxetine treatment; (ii) ADAR2 in astrocytes was decreased by the CMS but showed no response to fluoxetine in anhedonic animals; (iii) neither GluK2 expression in astrocytes nor 5-HT2CR expression in neurones were affected in anhedonic animals, although expression of 5-HT2CR mRNA was upregulated by fluoxetine. Our results indicate that the effects of chronic treatment with fluoxetine are not only dependent on the cell type studied but also on the development of anhedonia. This suggests that fluoxetine may affect major depression (MD) patients and healthy people in a different manner.
    Psychopharmacology 04/2015; 232(15). DOI:10.1007/s00213-015-3921-2 · 3.88 Impact Factor
    • "Reverse translation using knowledge about the mechanisms of human disorders has been used to identify and develop animals that have the molecular and cellular abnormalities found in these diseases (Malkesman et al., 2009). For example, depression has been modeled in mice having point mutations in the mitochondrial DNA polymerase (Kasahara et al., 2006) and glutamate receptor 6 knockout mice have a high face and predictive validity for mania (Shaltiel et al., 2008). " Lost in translation " has become a very popular paraphrase for the obstacles encountered in translational research. "
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    ABSTRACT: Many well-defined animal models for human disease are employed in modern preclinical and pathophysiology-driven research. However, the scientific community across all fields of modern biomedicine has become aware of weaknesses in current preclinical animal modeling. Here, we have outlined several strategies that have already been set into action to overcome the translational gap that is common to all current preclinical modeling of human disease.
    Principles of Translational Science in Medicine - From Bench to Bedside, 2nd Ed. edited by Martin Wehling, 04/2015: chapter Animal Models: Value and Translational Potency: pages 83 - 90; Academic Press., ISBN: 978-0-12-800721-1
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    • "The difficulties to model the complex symptomatology of BPD in animals have been a major obstacle for investigating the neurobiology of this condition. Although different models mimic manic-or depressive-like behavior (Dao, et al 2010; Engel, et al 2009; Han, et al 2013; Roybal, et al 2007; Shaltiel, et al 2008), few animal paradigms provide insights into the major characteristics of BPD, emotional lability, and behavioral fluctuations. Overexpressing glucocorticoid receptors in the forebrain of mice leads to depressive-like behavior, supersensitivity to antidepressants, and enhanced sensitization for cocaine, indicating that emotional lability can be caused by aberrant glucocorticoid signaling (Wei, et al 2004). "
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    ABSTRACT: Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2014; 40(4). DOI:10.1038/npp.2014.244 · 7.05 Impact Factor
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