Relationship between Rgs2 gene expression level and anxiety and depression-like behaviour in a mutant mouse model: serotonergic involvement

Abstract

RGS2 is a member of a family of proteins that negatively modulate G-protein coupled receptor transmission. Variations in the RGS2 gene were found to be associated in humans with anxious and depressive phenotypes. We sought to study the relationship of Rgs2 expression level to depression and anxiety-like behavioural features, sociability and brain 5-HT1A and 5-HT1B receptor expression. We studied male mice carrying a mutation that causes lower Rgs2 gene expression, employing mice heterozygous (Het) or homozygous (Hom) for this mutation, or wild-type (WT). Mice were subjected to behavioural tests reflecting depressive-like behaviour [forced swim test (FST), novelty suppressed feeding test (NSFT)], elevated plus maze (EPM) for evaluation of anxiety levels and the three-chamber sociability test. The possible involvement of raphe nucleus 5-HT1A receptors in these behavioural features was examined by 8-OH-DPAT-induced hypothermia. Expression levels of 5-HT1A and 5-HT1B receptors in the cortex, raphe nucleus and hypothalamus were compared among mice of the different Rgs2 genotype groups. NSFT results demonstrated that Hom mice showed more depressive-like features than Rgs2 Het and WT mice. A trend for such a relationship was also suggested by the FST results. EPM and sociability test results showed Hom and Het mice to be more anxious and less sociable than WT mice. In addition Hom and Het mice were characterized by lower basal body temperature and demonstrated less 8-OH-DPAT-induced hypothermia than WT mice. Finally, Hom and Het mice had significantly lower 5-HT1A and 5-HT1B receptor expression levels in the raphe than WT mice. Our findings demonstrate a relationship between Rgs2 gene expression level and a propensity for anxious and depressive-like behaviour and reduced social interaction that may involve changes in serotonergic receptor expression.

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

“…Even though no mechanisms were elucidated in how RGS2 might control the various responses in organs, the knockout mice provided a foundation for understanding the physiological functions of RGS2 (Tuomi et al, 2010). Recent genetic quantitative trait analysis has shown that RGS2 is a gene that controls anxiety in mice and possibly humans (Hettema et al, 2013;Le-Niculescu et al, 2011;Lifschytz et al, 2012;Mouri et al, 2010;Muinos-Gimeno et al, 2011;Okimoto et al, 2012;Otowa et al, 2011;Stein et al, 2014;Yalcin et al, 2004).…”

Influence of RGS2 on Sertraline Treatment for Social Anxiety Disorder

“…Deletion of rgs2 in mice produces increased anxiety-related behavior (Lifschytz et al, 2012;Oliveira-Dos-Santos et al, 2000;Yalcin et al, 2004) and avoidance behavior in novel social situations (Lifschytz et al, 2012). Mice lacking rgs2 have also been reported to show reduced expression of 5HT 1a G protein-coupled presynaptic autoreceptors (thought to be involved in the therapeutic activity of SSRIs) in the raphe (Lifschytz et al, 2012). Of note, the G allele of rs4606, which we found to predict reduced sertraline response, has been associated with reduced expression of RGS2 (Semplicini et al, 2006).…”

“…Among other functions, RGS2 accelerates the deactivation of G proteins to reduce neuronal G protein-coupled receptor response to neurotransmitters including serotonin (Kimple et al, 2011). Deletion of rgs2 in mice produces increased anxiety-related behavior (Lifschytz et al, 2012;Oliveira-Dos-Santos et al, 2000;Yalcin et al, 2004) and avoidance behavior in novel social situations (Lifschytz et al, 2012). Mice lacking rgs2 have also been reported to show reduced expression of 5HT 1a G protein-coupled presynaptic autoreceptors (thought to be involved in the therapeutic activity of SSRIs) in the raphe (Lifschytz et al, 2012).…”

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

“…Multiple reports have shown a role for this RGS protein in modulating anxiety, with polymorphisms in RGS2 associated with generalized anxiety disorder (Smoller et al, 2008;Koenen et al, 2009;Hohoff et al, 2015), panic disorder Otowa et al, 2011;Hohoff et al, 2015), post-traumatic stress disorder , as well as suicide (Cui et al, 2008) in humans. Studies in mice have also shown an association between RGS2 and anxiety (Oliveira-Dos-Santos et al, 2000;Yalcin et al, 2004;Lifschytz et al, 2012;Okimoto et al, 2012) with decreased RGS2 expression causing anxiety (Oliveira-Dos-Santos et al, 2000;Lifschytz et al, 2012) and depression-like (Lifschytz et al, 2012) phenotypes. To better treat these diseases associated with RGS2, it is necessary to understand how RGS2 modulates synaptic plasticity and signaling.…”

“…Ga q at the RGS domain (Heximer et al, 1997;Ingi et al, 1998) Hippocampus (Han et al, 2006) Presynaptic in hippocampal pyramidal neurons (Han et al, 2006) Regulates short-term synaptic plasticity in the hippocampus (Han et al, 2006) Anxiety (Doupnik et al, 1997;Lifschytz et al, 2012;Okimoto et al, 2012;Hohoff et al, 2015) Ga i/o at the RGS domain (Ingi et al, 1998;Han et al, 2006) Striatum (Labouèbe et al, 2007) Postsynaptic in dopamine neurons in the VTA (Labouèbe et al, 2007) Disinhibits GABA-mediated inhibition of dopamine neurons in the VTA (Labouèbe et al, 2007) Depression (Lifschytz et al, 2012;Mandelli and Serretti, 2013) Amygdala (Okimoto et al, 2012) NA (Not available)…”