Evidence that Regulator of G‐Protein Signaling 5 Protein Modulates Emotional Behaviors in Adult Mice
Authors: Chrissobolis Sophocles , Guisinger Trevor , Norman Haval , Seeley Sarah , Rorabaugh Boyd , D'Souza Manoranjan 
Published: June 2021

Many actions of angiotensin II (Ang II), such as oxidative stress and inflammation in the cerebral vasculature and brain, are mediated by the Ang II type 1 receptor, a G‐protein coupled receptor (GPCR). Ang II‐induced brain inflammation may contribute to emotional abnormalities, such as anxiety and depression. Regulator of G‐protein signaling (RGS) proteins modulate responses to extracellular signals such as Ang II acting through GPCRs by terminating G‐protein activity. Among the many types of RGS proteins, RGS5 is expressed in the brain and vasculature and modulates Ang II‐induced pressor responses and vascular contractility. We hypothesized that RGS5 deficiency would worsen Ang II‐induced anxiety‐ and depression‐like behavior, cerebral vascular oxidative stress, and brain inflammation. Adult male wild‐type (RGS5+/+) and RGS5‐deficient (RGS5−/−) mice were treated with Ang II (1 mg/kg/d) or vehicle (saline) for 21 days using osmotic minipumps. Systolic blood pressure (SBP, measured using tail cuff), anxiety (measured using elevated plus maze) and depression (measured using tail suspension test)‐like behaviors, and spontaneous locomotor activity were assessed in conscious mice; superoxide levels (measured using chemiluminesence) were examined in isolated cerebral arteries, and protein expression of VCAM‐1, NOX4 and eNOS were examined in left brain hemispheres. SBP was lower in RGS5−/− compared to RGS5+/+ mice (SBP in RGS5+/+=153±3 mmHg, n=22; RGS5−/− =140±5 mmHg, n=23, P<0.05), suggesting that RGS5 contributes to blood pressure maintenance. Ang II treatment caused a greater increase in SBP in RGS5−/− vs RGS5+/+ mice (eg. ΔSBP at Day 17 in Ang II–treated RGS5+/+= 16±7mmHg, n=10; Ang II‐treated RGS5−/−= 37±5 mmHg, n=10, P<0.05), confirming that RGS5 modulates Ang II‐induced pressor responses. In vehicle‐treated RGS5−/− mice, anxiety‐like behavior was increased compared to vehicle‐treated RGS5+/+ mice (time spent in open arms [secs] in veh‐treated RGS5+/+=79±12, n=7; veh‐treated RGS5−/−=36±5, n=8, P<0.05), suggesting that RGS5 deficiency causes anxiety‐like behavior. There was no effect of Ang II treatment on anxiety‐like behavior in RGS5−/− mice when compared with Ang II‐treated RGS5+/+. RGS5 deficiency alone had no effect on depression‐like behavior, however combined RGS5 deficiency and Ang II treatment resulted in increased depression‐like behavior compared to Ang II treatment in RGS5+/+ mice (time immobilized [secs] in Ang II‐treated RGS5+/+=170±10, n=10; Ang II‐treated RGS5−/−=202±10, n=11, P<0.05). Ang II treatment or RGS5 deficiency had no effect on spontaneous locomotor activity, cerebrovascular superoxide levels, and protein expression of VCAM‐1, NOX4 and eNOS. Overall, these data suggest that RGS5 deficiency increases vulnerability to Ang II‐induced increases in blood pressure, and that RGS5 deficiency differentially influences Ang II‐induced anxiety‐ and depression‐like behaviors.Support or Funding InformationThis work was supported by a Bower, Bennet and Bennet Endowed Chair Research Award from the College of PharmacyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.