Role of hippocampal 5-HT1A receptors in the antidepressant-like phenotype of mice expressing RGS-insensitive Gαi2 protein

NEUROPHARMACOLOGY

卷:141

Article

Senese, Nicolas B.^1,2  Oginsky, Max^1,2  Neubig, Richard R.³  Ferrario, Carrie^1,2  Jutkiewicz, Emily M.^1,2  Traynor, John R.^1,2 

[1] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Edward F Domino Res Ctr, Ann Arbor, MI 48109 USA

[3] Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48823 USA

关键词: Hippocampus;    Antidepressant-like activity;    Serotonin receptor;    G proteins;    RGS proteins;   

DOI  :  10.1016/j.neuropharm.2018.09.002

来源: Elsevier

【 摘 要 】

A single base mutation in the G alpha(i2) protein (G184S) renders this G alpha subunit insensitive to the negative modulatory effects of Regulator of G-protein Signaling (RGS) proteins. Mice expressing this RGS insensitive (RGSi) variant of G alpha(i2) (RGSi G alpha(i2)) display a spontaneous antidepressant-like phenotype that is reversible by treatment with the 5-HT1A receptor (5-HT1AR) antagonist WAY100635. Here we test the hypothesis that increased activity of 5-HT1ARs in the hippocampus of RGSi G alpha(i2) knock-in mice is responsible for the expression of the observed antidepressant-like behavior. We administered the 5-HT1AR antagonist WAY100635 or the agonist 8-OH-DPAT via bilateral intra-hippocampal infusion cannulae and evaluated antidepressant-like behavior using the tail suspension test (TST). WAY100635 reversed the antidepressant-like phenotype of the RGSi G alpha(i2) knock-in mice and 8-OH-DPAT produced an antidepressant-like response in wild type mice that was blocked by systemic WAY100635. Furthermore, intra-hippocampal infusion of the RGS19/4 inhibitor CCG-203769 produced an antidepressant-like effect in female mice. Ex-vivo slice recording confirmed the 5-HT1AR-mediated decrease in hippocampal CAl pyramidal neuron excitability was enhanced in the RGSi G alpha(i2) knock-in mice. There was no change in hippocampal 5-HT1AR expression as measured by ligand binding but there was a compensatory reduction in G alpha i proteins. The findings demonstrate that RGS protein control of hippocampal 5-HT1AR signaling is necessary and sufficient to account for the antidepressant-like phenotype in the RGSi G alpha(i2) knock-in mice and that RGS proteins highly expressed in the hippocampus should be investigated as targets for novel antidepressant therapies.

【 授权许可】

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