Title

Evidence that regulator of g-protein signaling 5 protein modulates emotional behaviors in adult mice

Document Type

Conference Proceeding

Publication Date

4-1-2019

Abstract

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.

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