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RGS6 deficiency promotes anxiolytic and antidepressant behavior through potentiation of 5‐HT 1A R signaling
Abstract   Open access   Peer reviewed

RGS6 deficiency promotes anxiolytic and antidepressant behavior through potentiation of 5‐HT 1A R signaling

Adele Stewart, Biswanath Maity, Amanda M Wunsch, John A Wemmie and Rory A Fisher
The FASEB journal, Vol.27(S1)
04/2013
DOI: 10.1096/fasebj.27.1_supplement.1031.8
url
https://doi.org/10.1096/fasebj.27.1_supplement.1031.8View
Published (Version of record) Open Access

Abstract

Abstract only Targeting serotonin availability with SSRIs remains the most widely used treatment for major depression. However, the limited efficacy, delayed onset of action, and side effects of these drugs limit their clinical utility. Studies in mice expressing an RGS‐insensitive mutant (G148S) of Gα i2 implicated endogenous RGS proteins as key negative regulators of 5‐HT 1A receptors, whose activation is believed to underlie the beneficial effects of SSRIs, but failed to identify the specific RGS protein(s) involved. We show here that RGS6 −/− mice exhibit spontaneous anxiolytic and antidepressant behavior in multiple tests, a phenotype identical to mice expressing RGS‐insensitive Gα i2 and reversible by 5‐HT 1A R blockade. The effects of the SSRI fluvoxamine and 5‐HT 1A agonist 8‐OH‐DPAT were also potentiated in RGS6 +/− mice. Though increased phosphorylation of GSK3β in both cortex and hippocampus was observed in Gα i2 (G148S) knock‐ins, no difference in GSK3β, AKT, or MAPK activity was observed in RGS6 −/− mice despite robust expression of RGS6 in these tissues. This later result suggests that the behavioral phenotype in these two mouse strains likely occurs through a distinct 5‐HT 1A ‐dependent signaling cascade. Nevertheless, our results indicate that RGS6 inhibition may represent a viable means to treat mood disorders or enhance the efficacy of serotoninergic agents through selective potentiation of 5‐HT 1A signaling.

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