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

Abstract

A single base mutation in the Gα protein (G184S) renders this Gα subunit insensitive to the negative modulatory effects of Regulator of G-protein Signaling (RGS) proteins. Mice expressing this RGS insensitive (RGSi) variant of Gα (RGSi Gα) 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 Gα 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 Gα 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 CA1 pyramidal neuron excitability was enhanced in the RGSi Gα knock-in mice. There was no change in hippocampal 5-HT1AR expression as measured by ligand binding but there was a compensatory reduction in Gαi 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 Gα knock-in mice and that RGS proteins highly expressed in the hippocampus should be investigated as targets for novel antidepressant therapies.

The Role of G-proteins and G-protein Regulating Proteins in Depressive Disorders

“…Both the changes in hippocampal GSK3β and antidepressant-like behaviors observed in RGSi Gα i2 knock-in mice are fully reversed by pretreatment with a 5-HT1A receptor antagonist ( Talbot et al, 2010 ). Furthermore, direct application of this 5-HT1A receptor antagonist to the hippocampus of the RGSi Gα i2 knock-in mice reversed their antidepressant-like behavior ( Senese et al, 2018 ), suggesting that enhanced 5-HT1A receptor activity in the hippocampus is necessary for this behavior. Coupled with the fact that 5-HT1A receptor agonists produce more potent antidepressant-like effects in these animals, it appears that the loss of RGS control at Gα i2 promotes 5-HT1A receptor signaling leading to robust antidepressant-like effects.…”

“…Mice expressing an RGSi knock-in variant of Gα i2 display a profound antidepressant-like phenotype across a number of behavioral tests including tail suspension, forced swim, elevated plus maze and novelty induced hypophagia ( Talbot et al, 2010 ; Senese et al, 2018 ). These mice also have antidepressant-like signaling changes in the hippocampus and frontal cortex, including reduced glycogen synthase kinase 3 beta (GSK3β) activity ( Talbot et al, 2010 ).…”

“…Coupled with the fact that 5-HT1A receptor agonists produce more potent antidepressant-like effects in these animals, it appears that the loss of RGS control at Gα i2 promotes 5-HT1A receptor signaling leading to robust antidepressant-like effects. Mice heterozygous for RGSi Gα o also show antidepressant-like effects in the tail suspension test, but the GPCR involved is not the 5-HT1A receptor and remains unidentified ( Senese et al, 2018 ). The culprit in this case may be the delta opioid receptor (DOPR) since the potency of the delta agonist SNC80 to produce antidepressant-like effects is enhanced in these mice ( Dripps et al, 2018 ).…”

“…Interestingly, RGSi Gα i2 knock-in mice display enhancements of responses known to depend on 5-HT1A heteroreceptor activity (e.g., antidepressant-like behaviors, hippocampal GSK3β inhibition), but not responses dependent on 5-HT1A autoreceptor activity (e.g., hypothermia; Hillegaart, 1991 ; Matsuda et al, 1995 ; Li et al, 2004 ; Talbot et al, 2010 ). 5-HT1A receptor agonists also produce exaggerated responses in hippocampal neurons from these mice, with more robust 5-HT1A receptor dependent suppression of neuronal excitability observed in pyramidal neurons ( Senese et al, 2018 ). As the hippocampus does not contain 5-HT cell bodies ( Ren et al, 2018 ), this provides direct evidence for increased 5-HT1A heteroreceptor activity in these animals.…”

“…The RGS4 inhibitor CCG-203769 produces antidepressant-like effects on the tail suspension test in a mouse model ( Senese et al, 2018 ). As RGS4 knockout mice do not have behavioral changes on the tail suspension test ( Dripps et al, 2017 ), and loss of RGS4 inhibits the antidepressant-like effects of drugs with diverse mechanisms of action ( Stratinaki et al, 2013 ), RGS4 inhibition alone cannot explain the antidepressant-like effect of CCG-203769.…”