Fig. 1: Grk3^−/− mice exhibit deficits in working memory, psychosis-like behaviors, and altered dopaminergic transmission.

Working memory was assessed in Grk3^+/+ (n = 19) and Grk3^−/− (n = 20) mice by calculating the (A) % spontaneous alternations (P = 0.37) and (B) the % same arm return (P = 0.011). C The percent prepulse inhibition was influenced by genotype (effect of: prepulse intensity F(2,74) = 134.90, P < 0.0010; genotype F(1,37) = 1.27, P = 0.27; interaction F(2,74) = 4.20, P = 0.019) with deficits observed in Grk3^−/− mice (n = 20) as compared to Grk3^+/+ mice at 73 dB (n = 19; *P = 0.030 post hoc Fisher’s LSD), while (D) the startle magnitude was similar (P = 0.75). E Grk3^−/− mice (n = 17) showed significantly higher sensitivity to the locomotor effects of D-amphetamine (5 mg/kg) than Grk3^+/+ mice (n = 13) (effect of: time F_(5,140) = 18.54, P < 0.0010; genotype F_(1,28) = 4.94, P = 0.034; interaction F_(5,140) = 2.95, P = 0.014). F Calculation of the area under the curve following injection was made in order to measure the net effect of D-amphetamine administration on locomotor response. Grk3^−/− mice (n = 17) showed a stronger response to amphetamine with enhanced locomotion compared to Grk3^+/+ mice (n = 13) (Mann–Whitney U-test, P = 0.039). G Accumulation of striatal dopamine induced by amphetamine (2 mg/kg) as measured by in vivo microdialysis was increased in Grk3^−/− mice (n = 5) compared to Grk3^+/+ mice (n = 5) 30 min post infusion (effect of: time F(11,88)=13.52, P < 0.0010; genotype F(1,8) = 4.08, P = 0.078; interaction F(11,88) = 2.22, P = 0.020; ***P = 0.00080 post hoc Bonferroni). H In vivo electrophysiology of dopaminergic cells in the VTA shows increased number of detectable cells per track in Grk3^−/− mice (n = 6) compared to Grk3^+/+ mice (n = 7; P = 0.0012), (I) as well as increased firing rate (Grk3^+/+ n = 35 cells, Grk3^−/− n = 78 cells; P = 0.043) although no significant changes in (J) burst firing could be detected (Grk3^+/+ n = 35 cells, Grk3^−/− n = 78 cells; P = 0.56). Group comparisons in (A), (B), (D), (G), (H), and (I) were performed using a Mann–Whitney U-test. Group comparisons in (C) were performed using a repeated measures 2-way ANOVA followed by Fisher’s LSD post hoc test. Group comparisons in (E) and (F) were performed using a repeated measures 2-way ANOVA followed by Bonferroni’s post hoc test. All error bars represent standard error of means (SEM). All tests were two-tailed. *P < 0.05, and **P < 0.01, ***P < 0.001.